This application is the 371 of PCT/GB 99/01753, filed on Jun. 6, 1999.
The present invention relates to antibiotic compounds and in particular to antibiotic compounds containing a substituted oxazolidinone ring. This invention further relates to processes for their preparation, to intermediates useful in their preparation, to their use as therapeutic agents and to pharmaceutical compositions containing them.
The international microbiological community continues to express serious concern that the evolution of antibiotic resistance could result in strains against which currently available antibacterial agents will be ineffective. In general, bacterial pathogens may be classified as either Gram-positive or Gram-negative pathogens. Antibiotic compounds with effective activity against both Gram-positive and Gram-negative pathogens are generally regarded as having a broad spectrum of activity. The compounds of the present invention are regarded primarily as effective against Gram-positive pathogens because of their particularly good activity against such pathogens.
Gram-positive pathogens, for example Staphylococci, Enterococci, Streptococci and mycobacteria, are particularly important because of the development of resistant strains which are both difficult to treat and difficult to eradicate from the hospital environment once established. Examples of such strains are methicillin resistant staphylococcus (MRSA), methicillin resistant coagulase negative staphylococci (MRCNS), penicillin resistant Streptococcus pneumoniae and multiply resistant Enterococcus faecium.
The major clinically effective antibiotic for treatment of such resistant Gram-positive pathogens is vancomycin. Vancomycin is a glycopeptide and is associated with nephrotoxicity and ototoxicity. Furthermore, and most importantly, antibacterial resistance to vancomycin and other glycopeptides is also appearing. This resistance is increasing at a steady rate rendering these agents less and less effective in the treatment of Gram-positive pathogens.
Certain antibacterial compounds containing an oxazolidinone ring have been described in the art (for example, Walter A. Gregory et al in J.Med.Chem. 1990, 33, 2569-2578 and Chung-Ho Park et al in J.Med.Chem. 1992, 35, 1156-1165). Such antibacterial oxazolidinone compounds with a 5-methylacetamide sidechain may be subject to mammalian peptidase metabolism. Furthermore, bacterial resistance to known antibacterial agents may develop, for example, by (i) the evolution of active binding sites in the bacteria rendering a previously active pharmacophore less effective or redundant, and/or (ii) the evolution of means to chemically deactivate a given pharmacophore. Therefore, there remains an ongoing need to find new antibacterial agents with a favourable pharmacological profile, in particular for compounds containing new pharmacophores.
We have discovered a class of antibiotic compounds containing a new class of substituted oxazolidinone ring which has useful activity against Gram-positive pathogens including MRSA and MRCNS and, in particular, against various strains exhibiting resistance to vancomycin and against E. faecium strains resistant to both aminoglycosides and clinically used xcex2-lactams.
Accordingly the present invention provides a compound of the formula (I), or a pharmaceutically-acceptable salt, or an in-vivo-hydrolysable ester thereof, 
wherein X is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94 or xe2x80x94SO2xe2x80x94;
HET is a C-linked 5-membered heteroaryl ring containing 2 to 4 heteroatoms independently selected from N, O and S, which ring is optionally substituted on an available carbon atom by 1 or 2 substituents independently selected from (1-4C)alkyl, amino, (1-4C)alkylamino, (1-4C)alkoxy and halogen, and/or on an available nitrogen atom (provided that the ring is not thereby quaternised) by (1-4C)alkyl;
Q is selected from Q1 to Q9: 
wherein R2 and R3 are independently hydrogen or fluoro;
wherein A1 is carbon or nitrogen; B1 is O or S (or, in Q9 only, NH); Xq is O, S or Nxe2x80x94R1 (wherein R1 is hydrogen, (1-4C)alkyl or hydroxy-(1-4C)alkyl); and wherein in Q7 each A1 is independently selected from carbon or nitrogen, with a maximum of 2 nitrogen heteroatoms in the 6-membered ring, and Q7 is linked to T via any of the A1 atoms (when A1 is carbon), and linked in the 5-membered ring via the specified carbon atom, or via A1 when A1 is carbon; Q8 is linked to T via either of the specified carbon atoms in the 5-membered ring, and linked in the benzo-ring via either of the two specified carbon atoms on either side of the linking bond shown; and Q9 is linked via either of the two specified carbon atoms on either side of the linking bond shown;
wherein T is selected from the groups in (TA) to (TD) below (wherein AR1, AR2, AR2a, AR2b, AR3, AR3a, AR3b, AR4, AR4a, CY1 and CY2 are defined hereinbelow);
(TA) T is selected from the following groups:
(TAa) AR1, AR1-(1-4C)alkyl-, AR2(carbon linked), AR3;
(TAb) AR1-CH(OH), AR2-CH(OH)xe2x80x94, AR3-CH(OH)xe2x80x94;
(TAc) AR1-COxe2x80x94, AR2-COxe2x80x94, AR3-COxe2x80x94, AR4-COxe2x80x94;
(TAd) AR1-Oxe2x80x94, AR2-COxe2x80x94, AR3-Oxe2x80x94;
(TAe) AR1-S(O)qxe2x80x94, AR2-S(O)qxe2x80x94, AR3-S(O)qxe2x80x94 (q is 0.1 or 2);
(TAf) an optionally substituted N-linked (fully unsaturated) 5-membered heteroaryl ring system containing 1, 2 or 3 nitrogen atoms;
(TAg) a carbon linked tropol-3-one or tropol-4-one, optionally substituted in a position not adjacent to the linking position; or
(TB) T is selected from the following groups:
(TBa) halo or (1-4C)alkyl
{optionally substituted by one or more groups each independently selected from hydroxy, (1-4C)alkoxy, (1-4C)alkanoyl, cyano, halo, trifluoromethyl, (1-4C)alkoxycarbonyl, xe2x80x94NRvRw, (1-6C)alkanoylamino, (1-4C)alkoxycarbonylamino, Nxe2x80x94(1-4C)alkyl-Nxe2x80x94(1-6C)alkanoylamino, (1-4C)alkylS(O)qxe2x80x94 (q is 0, 1 or 2), CY1, CY2 or AR1};
(TBb) xe2x80x94NRv1Rw1;
(TBc) ethenyl, 2-(1-4C)alkylethenyl, 2-cyanoethenyl, 2-cyano-2-(1-4C)alkyl)ethenyl, 2-nitroethenyl, 2-nitro-2-(1-4C)alkyl)ethenyl, 2-((1-4C)alkylaminocarbonyl)ethenyl, 2-((1-4C)alkoxycarbonyl)ethenyl, 2-(AR1)ethenyl, 2-(AR2)ethenyl;
(TBd) R10COxe2x80x94, R10S(O)qxe2x80x94 (q is 0, 1 or 2) or R10CSxe2x80x94
wherein R10 is selected from the following groups:
(TBda) CY1 or CY2;
(TBdb) hydrogen, (1-4C)alkoxycarbonyl, trifluoromethyl, xe2x80x94NRvRw, ethenyl, 2-(1-4C)alkylethenyl, 2-cyanoethenyl, 2-cyano-2-((1-4C)alkyl)ethenyl, 2-nitroethenyl, 2-nitro-2-((1-4C)alkyl)ethenyl, 2-(1-4C)alkylaminocarbonyl)ethenyl, 2-((1-4C)alkoxycarbonyl)ethenyl, 2-(AR1)ethenyl or 2-(AR2)ethenyl; or
(TBdc) (1-4C)alkyl {optionally substituted as defined in (TBa) above, or by (1-4C)alkylS(O)pNHxe2x80x94 or (1-4C)alkylS(O)pxe2x80x94((1-4C)alkyl)Nxe2x80x94 (p is 1 or 2)};
wherein Rv is hydrogen or (1-4C)alkyl; Rw is hydrogen or (1-4C)alkyl; Rv1 is hydrogen, (1-4C)alkyl or (3-8C)cycloalkyl; Rw1 is hydrogen, (1-4C)alkyl, (3-8C)cycloalkyl, (1-4C)alkyl-COxe2x80x94 or (1-4C)alkylS(O)qxe2x80x94 (q is 1 or 2); or
(TC) T is selected from the following groups:
(TCa) an optionally substituted, fully saturated 4-membered monocyclic ring containing 1 heteroatom selected from O, N and S (optionally oxidised), and linked via a ring nitrogen or sp3 carbon atom;
(TCb) an optionally substituted 5-membered monocyclic ring containing 1 heteroatom selected from O, N and S (optionally oxidised), and linked via a ring nitrogen atom or a ring sp3 or sp2 carbon atom, which monocyclic ring is fully saturated other than (where appropriate) at a linking sp2 carbon atom;
(TCc) an optionally substituted 6- or 7-membered monocyclic ring containing 1 or 2 heteroatoms independently selected from O, N and S (optionally oxidised), and linked via a ring nitrogen atom or a ring sp3 or sp2 carbon atom, which monocyclic ring is fully saturated other than (where appropriate) at a linking sp2 carbon atom; or
(TD) T is selected from the following groups:
(TDa) a bicyclic spiro-ring system containing 0, 1 or 2 ring nitrogen atoms as the only ring heteroatoms, the structure consisting of a 5- or 6-membered ring system (linked via a ring nitrogen atom or a ring sp3 or sp2 carbon atom) substituted (but not adjacent to the linking position) by a 3-, 4- or 5-membered spiro-carbon-linked ring; which bicyclic ring system is
(i) fully saturated other than (where appropriate) at a linking sp2 carbon atom;
(ii) contains one xe2x80x94N(Rc)xe2x80x94 group in the ring system (at least two carbon atoms away from the linking position when the link is via a nitrogen atom or an sp2 carbon atom) or one xe2x80x94N(Rc)xe2x80x94 group in an optional substituent (not adjacent to the linking position) and is
(iii) optionally further substituted on an available ring carbon atom; or
(TDb) a 7-, 8- or 9-membered bicyclic ring system (linked via a ring nitrogen atom or a ring sp3 or sp2 carbon atom) containing 0, 1 or 2 ring nitrogen atoms (and optionally a further O or S ring heteroatom), the structure containing a bridge of 1, 2 or 3 carbon atoms; which bicyclic ring system is
(i) fully saturated other than (where appropriate) at a linking sp2 carbon atom;
(ii) contains one O or S heteroatom, or one xe2x80x94N(Rc)xe2x80x94 group in the ring (at least two carbon atoms away from the linking position when the link is via a nitrogen atom or an s carbon atom) or one xe2x80x94N(Rc)xe2x80x94 group in an optional substituent (not adjacent to the linking position) and is
(iii) optionally further substituted on an available ring carbon atom;
wherein Rc is selected from groups (Rc1) to (Rc5):
(Rc1) (1-6C)alkyl {optionally substituted by one or more (1-4C)alkanoyl groups (including geminal disubstitution) and/or optionally monosubstituted by cyano, (1-4C)alkoxy, trifluoromethyl, (1-4C)alkoxycarbonyl, phenyl (optionally substituted as for AR defined hereinafter), (1-4C)alkylS(O)qxe2x80x94 (q is 0, 1 or 2); or, on any but the first carbon atom of the (1-6C)alkyl chain, optionally substituted by one or more groups (including geminal disubstitution) each independently selected from hydroxy and fluoro, and/or optionally monosubstituted by oxo, xe2x80x94NRvRw [wherein Rv is hydrogen or (1-4C)alkyl; Rw is hydrogen or (1-4C)alkyl], (1-6C)alkanoylamino, (1-4C)alkoxycarbonylamino, Nxe2x80x94(1-4C)alkyl-Nxe2x80x94(1-6C)alkanoylamino, (1-4C)alkylS(O)pNHxe2x80x94 or (1-4C)alkylS(O)pxe2x80x94((1-4C)alkyl)Nxe2x80x94 (p is 1 or 2)};
(Rc2) R13COxe2x80x94, R13SO2xe2x80x94 or R13CSxe2x80x94
wherein R13 is selected from (Rc2a) to (Rc2e):
(Rc2a) AR1, AR2, AR2a, AR2b, AR3, AR3a, AR3b, AR4, AR4a, CY1, CY2;
(Rc2b) hydrogen, (1-4C)alkoxycarbonyl, trifluoromethyl, xe2x80x94NRvRw [wherein Rv is hydrogen or (1-4C)alkyl; Rw is hydrogen or (1-4C)alkyl], ethenyl, 2-(1-4C)alkylethenyl, 2-cyanoethenyl, 2-cyano-2-(1-4C)alkyl)ethenyl, 2-nitroethenyl, 2-nitro-2-(1-4C)alkyl)ethenyl, 2-((1-4C)alkylaminocarbonyl)ethenyl, 2-(1-4C)alkoxycarbonyl)ethenyl, 2-(AR1)ethenyl, 2-(AR2)ethenyl, 2-(AR2a)ethenyl;
(Rc2c) (1-10C)alkyl {optionally substituted by one or more groups (including geminal disubstitution) each independently selected from hydroxy, (1-10C)alkoxy, (1-4C)alkoxy-(1-4C)alkoxy, (1-4C)alkoxy-(1-4C)alkoxy-(1-4C)alkoxy, (1-4C)alkanoyl, phosphoryl [xe2x80x94Oxe2x80x94P(O)(OH)2, and mono- and di-(1-4C)alkoxy derivatives thereof], phosphiryl [xe2x80x94Oxe2x80x94P(OH)2 and mono- and di-(1-4C)alkoxy derivatives thereof], and amino; and/or optionally substituted by one group selected from phosphonate [phosphono, xe2x80x94P(O)(OH)2, and mono- and di-(1-4C)alkoxy derivatives thereof], phosphinate [xe2x80x94P(OH)2 and mono- and di-(1-4C)alkoxy derivatives thereof], cyano, halo, trifluoromethyl, (1-4C)alkoxycarbonyl, 1-4C)alkoxy-(1-4C)alkoxycarbonyl, (1-4C)alkoxy-(1-4C)alkoxy-(1-4C)alkoxycarbonyl, (1-4C)alkylamino, di((1-4C)alkyl)amino, (1-6C)alkanoylamino, (1-4C)alkoxycarbonylamino, Nxe2x80x94(1-4C)alkyl-Nxe2x80x94(1-6C)alkanoylamino, (1-4C)alkylaminocarbonyl, di((1-4C)alkyl)aminocarbonyl, (1-4C)alkylS(O)pxe2x80x94((1-4C)alkyl)Nxe2x80x94, fluoro(1-4C)alkylS(O)pNHxe2x80x94, fluoro(1-4C)alkylS(O)p((1-4C)alkyl)Nxe2x80x94, (1-4C)alkylS(O)qxe2x80x94, CY1, CY2, AR1, AR2, AR3, AR1-Oxe2x80x94, AR2-Oxe2x80x94, AR3-Oxe2x80x94, AR1-S(O)qxe2x80x94, AR2-S(O)qxe2x80x94, AR3-S(O)qxe2x80x94, AR1-NHxe2x80x94, AR2-NHxe2x80x94, AR3-NHxe2x80x94 (p is 1 or 2 and q is 0, 1 or 2), and also AR2a, AR2b, AR3a and AR3b versions of AR2 and AR3 containing groups};
(Rc2d) R14C(O)O(1-6C)alkyl wherein R14 is AR1, AR2, (1-4C)alkylamino, benzyloxy-(1-4C)alkyl or (1-10C)alkyl {optionally substituted as defined for (Rc2c)};
(Rc2e) R15Oxe2x80x94 wherein R15 is benzyl, (1-6C)alkyl {optionally substituted as defined for (Rc2c)}, CY1, CY2 or AR2b;
(Rc3) hydrogen, cyano, 2-cyanoethenyl, 2-cyano-2-(1-4C)alkyl)ethenyl, 2-((1-4C)alkylaminocarbonyl)ethenyl, 2-((1-4C)alkoxycarbonyl)ethenyl, 2-nitroethenyl, 2-nitro-2-((1-4C)alkyl)ethenyl, 2-(AR1)ethenyl, 2-(AR2)ethenyl, or of the formula (Rc3a) 
wherein X00 is xe2x80x94OR17, xe2x80x94SR17, xe2x80x94NHR17and xe2x80x94N(R17)2;
wherein R17 is hydrogen (when X00 is xe2x80x94NHR17 and xe2x80x94N(R17)2), and R17 is (1-4C)alkyl, phenyl or AR2 (when X00 is xe2x80x94OR17, xe2x80x94SR17 and xe2x80x94NHR17); and R16 is cyano, nitro, (1-4C)alkylsulfonyl, (4-7C)cycloalkylsulfonyl, phenylsulfonyl, (1-4C)alkanoyl and (1-4C)alkoxycarbonyl;
(Rc4) trityl, AR1, AR2, AR2a, AR2b, AR3, AR3a, AR3b;
(Rc5) RdOC(Re)xe2x95x90CH(Cxe2x95x90O)xe2x80x94, RfC(xe2x95x90O)C(xe2x95x90O)xe2x80x94, RgNxe2x95x90C(Rh)C(xe2x95x90O)xe2x80x94 or RiNHC(Rj)xe2x95x90CHC(xe2x95x90O)xe2x80x94 wherein Rd is (1-6C)alkyl; Re is hydrogen or (1-6C)alkyl, or Rd and Re together form a (3-4C)alkylene chain; Rf is hydrogen, (1-6C)alkyl, hydroxy(1-6C)alkyl, (1-6C)alkoxy(1-6C)alkyl, xe2x80x94NRvRw [wherein Rv is hydrogen or (1-4C)alkyl; Rw is hydrogen or (1-4C)alkyl], (1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkoxy, hydroxy(2-6C)alkoxy, (1-4C)alkylamino(2-6C)alkoxy, di-(1-4C)alkylamino(2-6C)alkoxy; Rg is (1-6C)alkyl, hydroxy or (1-6C)alkoxy; Rh is hydrogen or (1-6C)alkyl; Ri is hydrogen, (1-6C)alkyl, AR1, AR2, AR2a, AR2b and Rj is hydrogen or (1-6C)alkyl;
wherein
AR1 is an optionally substituted phenyl or optionally substituted naphthyl;
AR2 is an optionally substituted 5- or 6-membered, fully unsaturated (i.e with the maximum degree of unsaturation) monocyclic heteroaryl ring containing up to four heteroatoms independently selected from O, N and S (but not containing any Oxe2x80x94O, Oxe2x80x94S or Sxe2x80x94S bonds), and linked via a ring carbon atom, or a ring nitrogen atom if the ring is not thereby quaternised;
AR2a is a partially hydrogenated version of AR2 (i.e. AR2 systems retaining some, but not the full, degree of unsaturation), linked via a ring carbon atom or linked via a ring nitrogen atom if the ring is not thereby quaternised;
AR2b is a fully hydrogenated version of AR2 (i.e. AR2 systems having no unsaturation), linked via a ring carbon atom or linked via a ring nitrogen atom;
AR3 is an optionally substituted 8-, 9- or 10-membered, fully unsaturated (i.e with the maximum degree of unsaturation) bicyclic heteroaryl ring containing up to four heteroatoms independently selected from O, N and S (but not containing any Oxe2x80x94O, Oxe2x80x94S or Sxe2x80x94S bonds), and linked via a ring carbon atom in either of the rings comprising the bicyclic system;
AR3a is a partially hydrogenated version of AR3 (i.e. AR3 systems retaining some, but not the full, degree of unsaturation), linked via a ring carbon atom, or linked via a ring nitrogen atom if the ring is not thereby quaternised, in either of the rings comprising the bicyclic system;
AR3b is a fully hydrogenated version of AR3 (i.e. AR3 systems having no unsaturation), linked via a ring carbon atom, or linked via a ring nitrogen atom, in either of the rings comprising the bicyclic system;
AR4 is an optionally substituted 13- or 14-membered, fully unsaturated (i.e with the maximum degree of unsaturation) tricyclic heteroaryl ring containing up to four heteroatoms independently selected from O, N and S (but not containing any Oxe2x80x94O, Oxe2x80x94S or Sxe2x80x94S bonds), and linked via a ring carbon atom in any of the rings comprising the tricyclic system;
AR4a is a partially hydrogenated version of AR4 (i.e. AR4 systems retaining some, but not the full, degree of unsaturation), linked via a ring carbon atom, or linked via a ring nitrogen atom if the ring is not thereby quaternised, in any of the rings comprising the tricyclic system;
CY1 is an optionally substituted cyclobutyl, cyclopentyl or cyclohexyl ring;
CY2 is an optionally substituted cyclopentenyl or cyclohexenyl ring.
In this specification, where it is stated that a ring may be linked via an sp2 carbon atom, which ring is fully saturated other than (where appropriate) at a linking sp2 carbon atom, it is to be understood that the ring is linked via a Cxe2x95x90C double bond.
In another embodiment, (Rc1) is as defined above other than the optional phenyl substituent on (1-6C)alkyl is optionally substituted as for AR1 defined hereinafter; and (Rc2c), is as defined above and further includes carboxy as an optional substituent on R13 as (1-10C)alkyl.
(TAf) When T is an optionally substituted N-linked (fully unsaturated) 5-membered heteroaryl ring system containing 1, 2 or 3 nitrogen atoms, it is preferably selected from a group of formula (TAf1) to (TAf6) below (particularly (TAf1), (TA2), (TAf4) and (TAf5), and especially (TAf1) and/or (TAf2)). The above preferred values of (TAf) are particularly preferred when present in Q1 or Q2, especially Q1, and when X is xe2x80x94Oxe2x80x94. 
wherein:
R6 is selected (independently where appropriate) from hydrogen, (1-4C)alkyl, (1-4C)alkoxycarbonyl, (1-4C)alkanoyl, carbamoyl and cyano;
R4 and R5 are independently selected from hydrogen, halo, trifluoromethyl, cyano, nitro, (1-4C)alkoxy, (1-4C)alkylS(O)qxe2x80x94 (q is 0, 1 or 2), (1-4C)alkanoyl, (1-4C)alkoxycarbonyl, (2-4C)alkanoyloxy-(1-4C)alkyl, benzoxy-(1-4C)alkyl, (2-4C)alkanoylamino, xe2x80x94CONRvRw, xe2x80x94NRvRw and (1-4C)alkyl {optionally substituted by hydroxy, trifluoromethyl, cyano, nitro, (1-4C)alkoxy, (1-4C)alkylS(O)qxe2x80x94 (q is 0, 1 or 2), (1-4C)alkoxycarbonyl, (1-4C)alkanoylamino, xe2x80x94CONRvRw, xe2x80x94NRvRw; wherein RvRw is hydrogen or (1-4C)alkyl; Rw is hydrogen or (1-4C)alkyl};
or R4 is selected from one of the groups in (TAfa) to (TAfc) below, or (where appropriate) one of R4 and R5 is selected from the above list of R4 and R5 values, and the other is selected from one of the groups in (TAfa) to (TAfc) below:
(TAfa) a group of the formula (TAfa1) 
wherein Z0 is hydrogen or (1-4C)alkyl;
X0 and Y0 are independently selected from hydrogen, (1-4C)alkyl, (1-4C)alkoxycarbonyl, halo, cyano, nitro, (1-4C)alkylS(O)qxe2x80x94 (q is 0, 1 or 2), RvRwNSO2xe2x80x94, trifluoromethyl, pentafluoroethyl, (1-4C)alkanoyl and xe2x80x94CONRvRw [wherein Rv is hydrogen or (1-4C)alkyl;
Rw is hydrogen or (1-4C)alkyl); or
one of X0 and Y0 is selected from the above list of X0 and Y0 values, and the other is selected from phenyl, phenylcarbonyl, xe2x80x94S(O)q-phenyl (q is 0, 1 or 2), N-(phenyl)carbamoyl, phenylaminosulfonyl, AR2, (AR2)-COxe2x80x94, (AR2)-S(O)qxe2x80x94 (q is 0, 1 or 2), N-(AR2)carbamoyl and (AR2)aminosulfonyl; wherein any phenyl group in (TAfa) may be optionally substituted by up to three substituents independently selected from (1-4C)alkyl, cyano, trifluoromethyl, nitro, halo and (1-4C)alkylsulfonyl;
(TAfb) an acetylene of the formula xe2x80x94xe2x89xa1xe2x80x94H or xe2x80x94xe2x89xa1xe2x80x94(1-4C)alkyl;
(TAfc) xe2x80x94X1xe2x80x94Y1xe2x80x94AR2, xe2x80x94X1xe2x80x94Y1xe2x80x94AR2a, xe2x80x94X1xe2x80x94Y1xe2x80x94AR2b, xe2x80x94X1xe2x80x94Y1xe2x80x94AR3, xe2x80x94X1xe2x80x94Y1xe2x80x94AR3a or xe2x80x94X1xe2x80x94Y1xe2x80x94AR3b;
wherein X1 is a direct bond or xe2x80x94CH(OH)xe2x80x94 and
Y1 is xe2x80x94(CH2)mxe2x80x94, xe2x80x94(CH2)nxe2x80x94NHxe2x80x94(CH2)mxe2x80x94, xe2x80x94COxe2x80x94(CH2)mxe2x80x94, xe2x80x94CONHxe2x80x94(CH2)mxe2x80x94, xe2x80x94C(xe2x95x90S)NHxe2x80x94(CH2)mxe2x80x94 or xe2x80x94C(xe2x95x90O)Oxe2x80x94(CH2)mxe2x80x94;
or wherein X1 is xe2x80x94(CH2)nxe2x80x94 or xe2x80x94CH(Me)xe2x80x94(CH2)mxe2x80x94 and
Y1 is xe2x80x94(CH2)mxe2x80x94NHxe2x80x94(CH2)mxe2x80x94, xe2x80x94COxe2x80x94(CH2)mxe2x80x94, xe2x80x94CONHxe2x80x94(CH2)mxe2x80x94, xe2x80x94C(xe2x95x90S)NHxe2x80x94(CH2)mxe2x80x94, xe2x80x94C(xe2x95x90O)Oxe2x80x94(CH2)mxe2x80x94 or xe2x80x94S(O)qxe2x80x94(CH2)mxe2x80x94; 
or wherein X1 is xe2x80x94CH2Oxe2x80x94, xe2x80x94CH2NHxe2x80x94 or xe2x80x94CH2N((1-4C)alkyl)xe2x80x94 and
Y1 is xe2x80x94COxe2x80x94(CH2)m, xe2x80x94CONHxe2x80x94(CH2)mxe2x80x94 or xe2x80x94C(xe2x95x90S)NHxe2x80x94(CH2)mxe2x80x94; and additionally Y1 is xe2x80x94SO2xe2x80x94 when X1 is xe2x80x94CH2NHxe2x80x94 or xe2x80x94CH2N((1-4C)alkyl)xe2x80x94, and Y1 is xe2x80x94(CH2)mxe2x80x94 when X1 is xe2x80x94CH2Oxe2x80x94 or xe2x80x94CH2N((1-4C)alkyl)xe2x80x94; wherein n is 1, 2 or 3; m is 0, 1, 2 or 3 and q is 0, 1 or 2; and when Y1 is xe2x80x94(CH2)mxe2x80x94NHxe2x80x94(CH2)mxe2x80x94 each m is independently selected from 0, 1, 2 or 3.
It is to be understood that when a value for xe2x80x94X1xe2x80x94 is a two-atom link and is written, for example, as xe2x80x94CH2NHxe2x80x94 it is the left hand part (xe2x80x94CH2xe2x80x94 here) which is bonded to the group of formula (TAf1) to (TAf6) and the right hand part (xe2x80x94NHxe2x80x94 here) which is bonded to xe2x80x94Y1xe2x80x94 in the definition in (TAfc). Similarly, when xe2x80x94Y1xe2x80x94 is a two-atom link and is written, for example, as xe2x80x94CONHxe2x80x94 it is the left hand part of xe2x80x94Y1xe2x80x94(xe2x80x94COxe2x80x94 here) which is bonded to the right hand part of xe2x80x94X1xe2x80x94, and the right hand part of xe2x80x94Y1xe2x80x94(xe2x80x94NHxe2x80x94 here) which is bonded to the AR2, AR2a, AR2b, AR3, AR3a or AR3b moiety in the definition in (TAfc).
Preferably R6 is hydrogen or (1-4C)alkyl, and R4 and R5 are independently selected from hydrogen, (1-4C)alkyl or one of R4 and R5 is selected from group (TAfa). Other preferable substituents on the (TAf1) to (TAf6) are illustrated in the accompanying Examples.
(TAg) When T is a carbon linked tropol-3-one or tropol-4-one, optionally substituted in a position not adjacent to the linking position (TAg), it is preferably selected from a group of formula (TAg1), (TAg2) or (TAg3). The above preferred values of (TAg) are particularly preferred when present in Q1 or Q2, especially Q1, and when X is xe2x80x94Oxe2x80x94. 
wherein R7 is selected from
(TAga)hydrogen, (1-4C)alkyl {optionally substituted by one or two substituents (excluding geminal disubstitution) independently selected from fluoro, hydroxy, (1-4C)alkoxy and xe2x80x94NRvRw]}; or
(TAgb)R8xe2x80x94Oxe2x80x94, R8xe2x80x94Sxe2x80x94, R8xe2x80x94NHxe2x80x94 or R8R8xe2x80x94Nxe2x80x94;
wherein R8 is selected (independently where appropriate) from hydrogen, (1-4C)alkyl or (3-8C)cycloalkyl {both optionally substituted by one or two substituents (excluding geminal disubstitution) independently selected from hydroxy, (1-4C)alkoxy, (1-4C)alkoxycarbonyl and xe2x80x94NRvRw}, (2-4C)alkenyl {optionally substituted by one or two xe2x80x94NRvRw substituents}, (1-4C)alkanoyl {optionally substituted by one or two substituents independently selected from xe2x80x94NRvRw and hydroxy}, phenyl-(1-4C)alkyl or pyridyl-(1-4C)alkyl {the phenyl and pyridyl (preferably pyridin-4-yl) rings being optionally substituted by one or two xe2x80x94NRvRw substituents}; or
(TAgc)morpholino, thiomorpholino, pyrrolidino {optionally independently substituted in the 3- and/or 4-positions by (1-4C)alkyl}, piperidino substituted in the 4-position by R9xe2x80x94, R9xe2x80x94Oxe2x80x94, R9xe2x80x94Sxe2x80x94, R9xe2x80x94NHxe2x80x94 or R9R9xe2x80x94Nxe2x80x94; wherein R9 is selected (independently where appropriate) from hydrogen, (1-4C)alkyl {optionally substituted by one or two (excluding geminal disubstitution) hydroxy, (1-4C)alkoxy, (1-4C)alkoxycarbonyl or xe2x80x94NRvRw} and piperazino {optionally substituted in the 4-position by (1-4C)alkyl, (3-8C)cycloalkyl, (1-4C)alkanoyl, (1-4C)alkoxycarbonyl or (1-4C)alkylsulfonyl, and optionally independently substituted in the 3- and/or 5-positions by (1-4C)alkyl}; wherein Rv is hydrogen or (1-4C)alkyl; Rw is hydrogen or (1-4C)alkyl.
(TC) Preferred values for the optional substituents and groups defined in (TCa) to (TCc) are defined by formulae (TC1) to (TC4): 
wherein in (TC1):  greater than A3xe2x80x94B3xe2x80x94 is  greater than C(Rq)xe2x80x94CH(Rr)xe2x80x94 and G is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94 or  greater than N(Rc);
wherein in (TC2): m1 is 0, 1 or 2;  greater than A3xe2x80x94B3xe2x80x94 is  greater than Cxe2x95x90C(Rr)xe2x80x94 or  greater than C(Rq)xe2x80x94CH(Rr)xe2x80x94 and G is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94 or  greater than N(Rc);
wherein in (TC3) m1 is 0, 1 or 2;  greater than A3xe2x80x94B3xe2x80x94 is  greater than C(Rq)xe2x80x94CH(Rr)xe2x80x94 (other than when Rq and Rr are both together hydrogen) and G is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94 or  greater than N(Rc);
wherein in (TC4): n1 is 1 or 2; o1 is 1 or 2 and n1+o1=2 or 3;  greater than A3xe2x80x94B3xe2x80x94 is  greater than Cxe2x95x90C(Rr)xe2x80x94 or  greater than C(Rq)xe2x80x94CH(Rr)xe2x80x94 or  greater than Nxe2x80x94CH2xe2x80x94 and G is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94 or  greater than N(Rc); Rp is hydrogen, (1-4C)alkyl (other than when such substitution is defined by  greater than A3xe2x80x94B3xe2x80x94), hydroxy, (1-4C)alkoxy or (1-4C)alkanoyloxy;
wherein in (TC1), (TC2) and (TC4); m1, n1 and o1 are as defined hereinbefore:  greater than A3xe2x80x94B3xe2x80x94 is  greater than Nxe2x80x94CH2xe2x80x94 and G is  greater than C(R11)(R12),  greater than Cxe2x95x90O,  greater than Cxe2x80x94OH,  greater than Cxe2x80x94(1-4C)alkoxy,  greater than Cxe2x95x90Nxe2x80x94OH,  greater than Cxe2x95x90Nxe2x80x94(1-4C)alkoxy,  greater than Cxe2x95x90Nxe2x80x94NHxe2x80x94(1-4C)alkyl,  greater than Cxe2x95x90Nxe2x80x94N(1-4C)alkyl)2 (the last two (1-4C)alkyl groups above in G being optionally substituted by hydroxy) or  greater than Cxe2x95x90Nxe2x80x94Nxe2x80x94COxe2x80x94(1-4C)alkoxy; wherein  greater than  represents two single bonds;
Rq is hydrogen, hydroxy, halo, (1-4C)alkyl or (1-4C)alkanoyloxy;
Rr is (independently where appropriate) hydrogen or (1-4C)alkyl;
R11 is hydrogen, (1-4C)alkyl, fluoro(1-4C)alkyl, (1-4C)alkyl-thio-(1-4C)alkyl or hydroxy-(1-4C)alkyl and R12 is xe2x80x94[C(Rr)(Rr)]m2xe2x80x94N(Rr)(Rc) wherein m2 is 0, 1 or 2;
and, other than the ring substitution defined by G,  greater than A3xe2x80x94B3xe2x80x94 and Rp, each ring system may be optionally further substituted on a carbon atom not adjacent to the link at  greater than A3xe2x80x94 by up to two substituents independently selected from (1-4C)alkyl, fluoro(1-4C)alkyl (including trifluoromethyl), (1-4C)alkyl-thio-(1-4C)alkyl, hydroxy-(1-4C)alkyl, amino, amino-(1-4C)alkyl, (1-4C)alkanoylamino, (1-4C)alkanoylamino-(1-4C)alkyl, carboxy, (1-4C)alkoxycarbonyl, AR-oxymethyl, AR-thiomethyl, oxo (xe2x95x90O) (other than when G is  greater than Nxe2x80x94Rc and Rc is group (Rc2) defined hereinbefore) or independently selected from Rc; and also hydroxy or halo (the last two optional substituents only when G is xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94);
wherein AR is as defined for formula (IP) hereinafter; Rc is selected from groups (Rc1) to (Rc5) defined hereinbefore.
For the avoidance of doubt, ( )m1, ( )n1 and ( )o1 indicate (xe2x80x94CH2xe2x80x94)m1, (xe2x80x94CH2xe2x80x94)n1 and (xe2x80x94CH2xe2x80x94)o1 respectively (optionally substituted as described above).
In the above definition of (TC1) to (TC4) and of the further optional substituents, AR is preferably AR2, and the further optional substituents are preferably not selected from the values listed for Rc. A preferred value for G is  greater than N(Rc) or  greater than C(R11)(R12).
Particularly preferred values for the optional substituents and groups defined in (TCa) to (TCc), and (TC1) to (TC4) are contained in the following definitions (TC5) to (TC11): 
wherein Rc has any of the values listed hereinbefore or hereinafter.
Especially preferred are (TC5), (TC6), (TC7) and (TC9), most especially (TC5) in which Rc has any of the values listed hereinbefore or hereinafter (especially R13COxe2x80x94 with the preferable R13 values given hereinafter). In (TC5) Rc is preferably selected from the group (Rc2), especially R13COxe2x80x94 with the preferable R13 values given hereinafter. In (TC7) Rc is preferably selected from group (Rc3) or (Rc4).
The above preferred values of (TCa) to (TCc) are particularly preferred when present in Q1 or Q2, especially Q1, and when X is xe2x80x94Oxe2x80x94 (especially when HET is isoxazole).
(TDa) When T is a bicyclic spiro-ring system as defined in (TDa), it is preferably selected from a group of formula (TDa1) to (TDa9). The above preferred values of(TDa) are particularly preferred when present in Q1 or Q2, especially Q1, and when X is xe2x80x94Oxe2x80x94. 
wherein;
(i) the A4 linking group is a nitrogen atom or an sp3 or sp2 carbon atom (with the double bond, where appropriate, orientated in either direction); and
(ii) one of the ring carbon atoms at positions marked * and ** is replaced by one of the following groups: xe2x80x94NRcxe2x80x94,  greater than CHxe2x80x94NHRc,  greater than CHxe2x80x94NRcxe2x80x94(1-4C)alkyl,  greater than CHxe2x80x94CH2xe2x80x94NHRc,  greater than CHxe2x80x94CH2xe2x80x94NRcxe2x80x94(1-4C)alkyl [wherein a central xe2x80x94CH2xe2x80x94 chain link is optionally mono- or di-substituted by (1-4C)alkyl]; with the provisos that positions marked * are not replaced by xe2x80x94NHxe2x80x94 in the ring containing the A4 link when A4 is a nitrogen atom or an sp2 carbon atom, and that positions marked * are not replaced by xe2x80x94NHxe2x80x94 in the three membered ring in (TDa1), (TDa4) and (TDa5); and
(iii) the ring system is optionally (further) substituted on an available ring carbon atom by up to two substituents independently selected from (1-4C)alkyl, fluoro(1-4C)alkyl (including trifluoromethyl), (1-4C)alkyl-thio-(1-4C)alkyl, hydroxy-(1-4C)alkyl, amino, amino-(1-4C)alkyl, (1-4C)alkanoylamino, (1-4C)alkanoylamino-(1-4C)alkyl, carboxy, (1-4C)alkoxycarbonyl, AR2-oxymethyl, AR2-thiomethyl, oxo (xe2x95x90O) (other than when the ring contains an  greater than Nxe2x80x94Rc and Rc is group (Rc2)) and also hydroxy or halo;
wherein Rc has any of the values listed hereinbefore or hereinafter.
(TDb) When T is a 7-, 8- or 9-membered bicyclic ring system containing a bridge of 1, 2 or 3 carbon atoms as defined in (TDb), it is preferably selected from a group defined by the ring skeletons shown in formulae (TDb1) to (TDb14): 
wherein;
(i) the ring system contains 0, 1 or 2 ring nitrogen atoms (and optionally a further O or S ring heteroatom), and when present the ring nitrogen, O or S heteroatom/s are at any position other than as part of the 3-membered ring in (TDb1);
(ii) the ring system is linked via a ring nitrogen atom or a ring sp3 or sp2 carbon atom (with the double bond, where appropriate, orientated in either direction) from any position in either ring [other than from a bridgehead position or from an sp2 carbon atom in the 4-membered ring in (TDb2), (TDb6) and (TDb11)];
(iii) one of the ring carbon atoms at a position not adjacent to the linking position, is replaced (other than when the ring contains an O or S heteroatom) by one of the following groups xe2x80x94NRcxe2x80x94 [not at a bridgehead position],  greater than C(H)xe2x80x94NHRc,  greater than C(H)xe2x80x94NRcxe2x80x94(1-4C)alkyl,  greater than C(H)xe2x80x94CH2xe2x80x94NHRc,  greater than C(H)xe2x80x94CH2xe2x80x94NRcxe2x80x94(1-4C)alkyl [wherein the hydrogen atom shown in brackets is not present when the replacement is made at a bridgehead position and wherein a central xe2x80x94CH2xe2x80x94 chain link is optionally mono- or di-substituted by (1-4C)alkyl]; with the proviso that when the ring system is linked via a ring nitrogen atom or an sp2 carbon atom any replacement of a ring carbon atom by xe2x80x94NRcxe2x80x94, O or S is at least two carbon atoms away from the linking position; and
(iv) the ring system is optionally (further) substituted on an available ring carbon atom as for the bicyclic spiro-ring systems described in (TDa); wherein Rc has any of the values listed hereinbefore or hereinafter.
It will be appreciated that unstable anti-Bredt compounds are not contemplated in this definition (i.e. compounds wraith structures (TDb3), (TDb4), (TDb7), (TDb8), (TDb9), (TDb12), (TDb13) and (TDb14) in which an sp2 carbon atom is directed towards a bridgehead position).
Particularly preferred values of (TDb) are the following structures of formula (TDb4), (TDb8) and/or (TDb9); wherein Rc has any of the values listed hereinbefore or hereinafter. The above preferred values of (TDb) are particularly preferred when present in Q1 or Q2, especially Q1, and when X is xe2x80x94Oxe2x80x94. 
In another embodiment there is provided a compound of the formula (I) which is defined by the formula (IP) below, or a pharmaceutically-acceptable salt or an in-vivo hydrolysable ester thereof, wherein
X is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94 or xe2x80x94SO2xe2x80x94;
HET is a C-linked 5-membered heteroaryl ring containing 2 or 3 heteroatoms independently selected from N, O and S (with the proviso that there are no Oxe2x80x94O, Oxe2x80x94S or Sxe2x80x94S bonds), which ring is optionally substituted on any available C atom (provided that when a N atom is adjacent to the X-link, there is no substitution on any C atom that is adjacent to this N atom) by 1 or 2 substituents independently selected from (1-4C)alkyl, amino, (1-4C)alkylamino, (1-4C)alkoxy and halogen, and/or on an available N atom (provided that the ring is not thereby quaternised), by (1-4C)alkyl; 
wherein: R2 and R3 are independently hydrogen or fluoro;
Rp is hydrogen, (1-4C)alkyl, hydroxy, (1-4C)alkoxy or (2-4C)alkanoyloxy;
 greater than Axe2x80x94Bxe2x80x94 is of the formula  greater than Cxe2x95x90C(Rr)xe2x80x94,  greater than CHCHRrxe2x80x94,  greater than C(OH)CHRrxe2x80x94 or  greater than Nxe2x80x94CH2xe2x80x94 ( greater than represents two single bonds) wherein Rr is hydrogen or (1-4C)alkyl;
D is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94 or  greater than NRcp;
Rp1 and Rp2 are independently oxo (xe2x95x90O) [but not when Rcp is group (PC) below], (1-4C)alkyl, (1-4C)alkanoylamino-(1-4C)alkyl, hydroxy-(1-4C)alkyl, carboxy, (1-4C)alkoxycarbonyl, AR-oxymethyl, AR-thiomethyl (wherein AR is as defined hereinbelow) or independently as defined for Rcp hereinbelow with the proviso that Rp1 and Rp2 are not phenyl, benzyl, AR (as defined hereinbelow), a tetrazole ring system, cyclopentyl or cyclohexyl; and when D is xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94, Rp1 and Rp2 are additionally independently hydroxy or bromo;
wherein Rcp is selected from (PA) to (PE) below:
(PA) hydrogen, cyano, 2-((1-4C)alkoxycarbonyl)ethenyl, 2-cyanoethenyl, 2-cyano-2-((1-4C)alkyl)ethenyl, 2-((1-4C)alkylaminocarbonyl)ethenyl;
(PB) phenyl, benzyl, AR (as defined hereinbelow) or a tetrazole ring system [optionally mono-substituted in the 1- or 2-position of the tetrazole ring by (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl or (1-4C)alkanoyl] wherein the tetrazole ring system is joined to the nitrogen in  greater than NRcp by a ring carbon atom;
(PC) R13pCOxe2x80x94, R13pSO2xe2x80x94 or R13pCSxe2x80x94 wherein R13p is selected from (PCa) to (PCf):
(PCa) AR (as defined hereinbelow);
(PCb) cyclopentyl or cyclohexyl, 1,3-dioxolan-4-yl, 1,3-dioxan-4-yl or 1,4-dioxan-2-yl [optionally mono- or di-substituted by substituents independently selected from (1-4C)alkyl (including geminal disubstitution), hydroxy (but excluding 1,3-dioxolan-4-yl, 1,3-dioxan-4-yl or 1,4-dioxan-2-yl substituted by hydroxy), (1-4C)alkoxy, (1-4C)alkylthio, acetamido, (1-4C)alkanoyl, cyano and trifluoromethyl];
(PCc) hydrogen, (1-4C)alkoxycarbonyl, trifluoromethyl, amino, (1-4C)alkylamino, di((1-4C)alkyl)amino, 2-(5- or 6-membered heteroaryl)ethenyl, 2-(5- or 6-membered (partially) hydrogenated heteroaryl)ethenyl, 2-phenylethenyl [wherein the heteroaryl or phenyl substituent is optionally substituted on an available carbon atom by up to three substituents independently selected from (1-4C)alkoxy, halo, cyano and (for the phenyl substituent only) (1-4C)alkylsulfonyl];
(PCd) (1-10C)alkyl [optionally substituted by one or more groups (including geminal disubstitution) each independently selected from hydroxy and amino, or optionally monosubstituted by cyano, halo, (1-10C)alkoxy, trifluoromethyl, (1-4C)alkoxy-(1-4C)alkoxy, (1-4C)alkoxy-(1-4C)alkoxy-(1-4C)alkoxy, (1-4C)alkanoyl, (1-4C)alkoxycarbonyl, (1-4C)alkylamino, di((1-4C)alkyl)amino, (1-6C)alkanoylamino, (1-4C)alkoxycarbonylamino, Nxe2x80x94(1-4C)alkyl-Nxe2x80x94(2-6C)alkanoylamino, (1-4C)alkylS(O)pNHxe2x80x94, (1-4C)alkylS(O)pxe2x80x94((1-4C)alkyl)Nxe2x80x94, fluoro(1-4C)alkylS(O)pNHxe2x80x94, fluoro(1-4C)alkylS(O)p((1-4C)alkyl)Nxe2x80x94, phosphono, (1-4C)alkoxy(hydroxy)phosphoryl, di-(1-4C)alkoxyphosphoryl, (1-4C)alkylS(O)qxe2x80x94, phenyl, naphthyl, phenoxy, naphthoxy, phenylamino, naphthylamino, phenylS(O)qxe2x80x94, naphthylS(O)qxe2x80x94 [wherein said phenyl and naphthyl groups are optionally substituted by up to three substituents independently selected from (1-4C)alkoxy, halo and cyano], or CY (as defined hereinbelow), wherein p is 1 or 2 and q is 0, 1 or 2];
(PCe) R14pC(O)O(1-6C)alkyl wherein R14p is an optionally substituted 5- or 6-membered heteroaryl, optionally substituted phenyl, (1-4C)alkylamino, benzyloxy-(1-4C)alkyl or optionally substituted (1-10C)alkyl;
(PCf) R15pOxe2x80x94 wherein R15p is benzyl or optionally substituted (1-6C)alkyl;
(PD) RdOC(Re)xe2x95x90CH(Cxe2x95x90O)xe2x80x94, RfC(xe2x95x90O)C(xe2x95x90O)xe2x80x94, RgNxe2x95x90C(Rh)C(xe2x95x90O)xe2x80x94 or RiNHC(Rj)xe2x95x90CHC(xe2x95x90O)xe2x80x94 wherein Rd is (1-6C)alkyl; Re is hydrogen or (1-6C)alkyl, or Rd and Re together form a (3-4C)alkylene chain; Rf is hydrogen, (1-6C)alkyl, hydroxy(1-6C)alkyl, (1-6C)alkoxy(1-6C)alkyl, amino, (1-4C)alkylamino, di-(1-4C)alkylamino, (1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkoxy, hydroxy(2-6C)alkoxy, (1-4C)alkylamino(2-6C)alkoxy, di-(1-4C)alkylamino(2-6C)alkoxy; Rg is (1-6C)alkyl, hydroxy or (1-6C)alkoxy; Rh is hydrogen or (1-6C)alkyl; Ri is hydrogen, (1-6C)alkyl, optionally substituted phenyl or an optionally substituted 5- or 6-membered heteroaryl [and (partially) hydrogenated versions thereof] and Rj is hydrogen or (1-6C)alkyl;
(PE) R16pCH(R17p)(CH2)mpxe2x80x94 wherein mp is 0 or 1; R17p is fluoro, cyano, (1-4C)alkoxy, (1-4C)alkylsulfonyl, (1-4C)alkoxycarbonyl or hydroxy, (provided that when mp is 0, R17p is not fluoro or hydroxy) and R16p is hydrogen or (1-4C)alkyl;
wherein AR is optionally substituted phenyl, optionally substituted phenyl(1-4C)alkyl, optionally substituted naphthyl, optionally substituted 5- or 6-membered heteroaryl;
wherein AR is also an optionally substituted 5/6 or 6/6 bicyclic heteroaryl ring system, in which the bicyclic heteroaryl ring systems may be linked via an atom in either of the rings comprising the bicyclic system, and wherein both the mono- and bicyclic heteroaryl ring systems are linked via a ring carbon atom and may be (partially) hydrogenated;
wherein CY is selected from:
(i) cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl or cyclohexenyl ring;
(ii) 5- or 6-membered heteroaryl, 5- or 6-membered heteroaryloxy, 5- or 6-membered heteroaryl-S(O)qxe2x80x94, 5- or 6-membered heteroarylamino [and (partially) hydrogenated versions thereof] and
(iii) 5/6 or 6/6 bicyclic heteroaryl, 5/6 or 6/6 bicyclic heteroaryloxy, 5/6 or 6/6 bicyclic heteroaryl-S(O)qxe2x80x94, 5/6 or 6/6 bicyclic heteroarylamino [and (partially) hydrogenated versions thereof]; wherein q is 0, 1 or 2 and any of the afore-mentioned ring systems in CY may be optionally substituted by up to three substituents independently selected from halo, (1-4C)alkyl [including geminal disubstitution when CY is a cycloalkyl or cycloalkenyl ring in (i)], acyl, oxo and nitro-(1-4C)alkyl.
For the avoidance of doubt, phosphono is xe2x80x94P(O)(OH)2; (1-4C)alkoxy(hydroxy)-phosphoryl is a mono-(1-4C)alkoxy derivative of xe2x80x94Oxe2x80x94P(O)(OH)2; and di-(1-4C)alkoxyphosphoryl is a di-(1-4C)alkoxy derivative of xe2x80x94Oxe2x80x94P(O)(OH)2.
In this embodiment of formula (IP) a xe2x80x985- or 6-membered heteroarylxe2x80x99 and xe2x80x98heteroaryl (monocyclic) ringxe2x80x99 means a 5- or 6-membered aryl ring wherein (unless stated otherwise) 1, 2 or 3 of the ring atoms are selected from nitrogen, oxygen and sulfur. Unless stated otherwise, such rings are fully aromatic. Particular examples of 5- or 6-membered heteroaryl ring systems are furan, pyrrole, pyrazole, imidazole, triazole, pyrimidine, pyridazine, pyridine, isoxazole, oxazole, isothiazole, thiazole and thiophene.
Particular examples of 5-membered heteroaryl rings containing 2 or 3 heteroatoms independently selected from N, O and S (with the proviso that there are no Oxe2x80x94O, Oxe2x80x94S or Sxe2x80x94S bonds; and in an alternative embodiment, also no Nxe2x80x94S bonds) are pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, oxazole, isoxazole, thiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole; and also in an alternative embodiment, isothiazole, 1,2,5-thiadiazole, 1,2,4-thiadiazole or 1,2,3-thiadiazole.
In this embodiment of formula (IP) a xe2x80x985/6 or 6/6 bicyclic heteroaryl ring systemxe2x80x99 and xe2x80x98heteroaryl (bicyclic) ringxe2x80x99 means an aromatic bicyclic ring system comprising a 6-membered ring fused to either a 5 membered ring or another 6 membered ring, the bicyclic ring system containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur. Unless stated otherwise, such rings are fully aromatic. Particular examples of 5/6 and 6/6 bicyclic ring systems are indole, benzofuran, benzimidazole, benzothiophene, benzisothiazole, benzoxazole, benzisoxazole, pyridoimidazole, pyrimidoimidazole, quinoline, quinoxaline, quinazoline, phthalazine, cinnoline and naphthyridine.
Particular optional substituents for alkyl, phenyl (and phenyl containing moieties) and naphthyl groups and ring carbon atoms in heteroaryl (mono or bicyclic) rings in R14p, R15p, Ri and AR include halo, (1-4C)alkyl, hydroxy, nitro, carbamoyl, (1-4C)alkylcarbamoyl, di-((1-4C)alkyl)carbamoyl, cyano, trifluoromethyl, trifluoromethoxy, amino, (1-4C)alkylamino, di((1-4C)alkyl)amino, (1-4C)alkyl S(O)qxe2x80x94 (q is 0, 1 or 2), carboxy, (1-4C)alkoxycarbonyl, (2-4C)alkenyl, (2-4C)alkynyl, (1-4C)alkanoyl, (1-4C)alkoxy, (1-4C)alkylS(O)2amino, (1-4C)alkanoylamino, benzoylamino, benzoyl, phenyl (optionally substituted by up to three substituents selected from halo, (1-4C)alkoxy or cyano), furan, pyrrole, pyrazole, imidazole, triazole, pyrimidine, pyridazine, pyridine, isoxazole, oxazole, isothiazole, thiazole, thiophene, hydroxyimino(1-4C)alkyl, (1-4C)alkoxyimino(1-4C)alkyl, hydroxy-(1-4C)alkyl, halo-(1-4C)alkyl, nitro(1-4C)alkyl, amino(1-4C)alkyl, cyano(1-4C)alkyl, (1-4C)alkanesulfonamido, aminosulfonyl, (1-4C)alkylaminosulfonyl and di-((1-4C)alkyl)aminosulfonyl. The phenyl and naphthyl groups and heteroaryl (mono- or bicyclic) rings in R14p, Ri and AR may be mono- or di-substituted on ring carbon atoms with substituents independently selected from the above list of particular optional substituents.
In this specification the term xe2x80x98alkylxe2x80x99 includes straight chained and branched structures. For example, (1-6C)alkyl includes propyl, isopropyl and tert-butyl. However, references to individual alkyl groups such as xe2x80x9cpropylxe2x80x9d are specific for the straight chained version only, and references to individual branched chain alkyl groups such as xe2x80x9cisopropylxe2x80x9d are specific for the branched chain version only. A similar convention applies to other radicals, for example halo(1-4C)alkyl includes 1-bromoethyl and 2-bromoethyl.
There follow particular and suitable values for certain substituents and groups referred to in this specification. These values may be used where appropriate with any of the definitions and embodiments disclosed hereinbefore, or hereinafter.
Examples of (1-4C)alkyl and (1-5C)alkyl include methyl, ethyl, and propyl and isopropyl; examples of (1-6C)alkyl include methyl, ethyl, propyl, isopropyl, pentyl and hexyl; examples of (1-10C)alkyl include methyl, ethyl, propyl, isopropyl, pentyl, hexyl, heptyl, octyl and nonyl; examples of (1-4C)alkanoylamino-1-4C)alkyl include formamidomethyl, acetamidomethyl and acetamidoethyl; examples of hydroxy(1-4C)alkyl and hydroxy(1-6C)alkyl include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl and 3-hydroxypropyl; examples of (1-4C)alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl; examples of 2-((1-4C)alkoxycarbonyl)ethenyl include 2-(methoxycarbonyl)ethenyl and 2-(ethoxycarbonyl)ethenyl; examples of 2-cyano-2-((1-4C)alkyl)ethenyl include 2-cyano-2-methylethenyl and 2-cyano-2-ethylethenyl; examples of 2-nitro-2-(1-4C)alkyl)ethenyl include 2-nitro-2-methylethenyl and 2-nitro-2-ethylethenyl; examples of 2-((1-4C)alkylaminocarbonyl)ethenyl include 2-(methylaminocarbonyl)ethenyl and 2-(ethylaminocarbonyl)ethenyl; examples of (2-4C)alkenyl include allyl and vinyl; examples of (2-4C)alkynyl include ethynyl and 2-propynyl; examples of (1-4C)alkanoyl include formyl, acetyl and propionyl; examples of (1-4C)alkoxy include methoxy, ethoxy and propoxy; examples of (1-6C)alkoxy and (1-10C)alkoxy include methoxy, ethoxy, propoxy and pentoxy; examples of (1-4C)alkylthio include methylthio and ethylthio; examples of (1-4C)alkylamino include methylamino, ethylamino and propylamino; examples of di-((1-4C)alkyl)amino include dimethylamino, N-ethyl-N-methylamino, diethylamino, N-methyl-N-propylamino and dipropylamino; examples of halo groups include fluoro, chloro and bromo; examples of (1-4C)alkylsulfonyl include methylsulfonyl and ethylsulfonyl; examples of (1-4C)alkoxy-1-4C)alkoxy and (1-6C)alkoxy-(1-6C)alkoxy include methoxymethoxy, 2-methoxyethoxy, 2-ethoxyethoxy and 3-methoxypropoxy; examples of (1-4C)alkoxy-(1-4C)alkoxy-(1-4C)alkoxy include 2-(methoxymethoxy)ethoxy, 2-(2-methoxyethoxy)ethoxy; 3-(2-methoxyethoxy)propoxy and 2-(2-ethoxyethoxy)ethoxy; examples of (1-4C)alkylS(O)2amino include methylsulfonylamino and ethylsulfonylamino; examples of(1-4C)alkanoylamino and (1-6C)alkanoylamino include formamido, acetamido and propionylamino; examples of (1-4C)alkoxycarbonylamino include methoxycarbonylamino and ethoxycarbonylamino; examples of Nxe2x80x94(1-4C)alkyl-Nxe2x80x94(1-6C)alkanoylamino include N-methylacetamido, N-ethylacetamido and N-methylpropionamido; examples of (1-4C)alkylS(O)pNHxe2x80x94 wherein p is 1 or 2 include methylsulfinylamino, methylsulfonylamino, ethylsulfinylamino and ethylsulfonylamino; examples of (1-4C)alkylS(O)p((1-4C)alkyl)Nxe2x80x94 wherein p is 1 or 2 include methylsulfinylmethylamino, methylsulfonylmethylamino, 2-(ethylsulfinyl)ethylamino and 2-(ethylsulfonyl)ethylamino; examples of fluoro(1-4C)alkylS(O)pNHxe2x80x94 wherein p is 1 or 2 include trifluoromethylsulfinylamino and trifluoromethylsulfonylamino; examples of fluoro(1-4C)alkylS(O)p((1-4C)alkyl)NHxe2x80x94 wherein p is 1 or 2 include trifluoromethylsulfinylmethylamino and trifluoromethylsulfonylmethlylamino examples of (1-4C)alkoxy(hydroxy)phosphoryl include methoxy(hydroxy)phosphoryl and ethoxy(hydroxy)phosphoryl; examples of di-(1-4C)alkoxyphosphoryl include di-methoxyphosphoryl, di-ethoxyphosphoryl and ethoxy(methoxy)phosphoryl; examples of (1-4C)alkylS(O)qxe2x80x94 wherein q is 0, 1 or 2 include methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, methylsulfonyl and ethylsulfonyl; examples of phenylS(O)q and naphthylS(O)qxe2x80x94 wherein q is 0, 1 or 2 are phenylthio, phenylsulfinyl, phenylsulfonyl and naphthylthio, naphthylsulfinyl and naphthylsulfonyl respectively; examples of benzyloxy-(1-4C)alkyl include benzyloxymethyl and benzyloxyethyl; examples of a (3-4C)alkylene chain are trimethylene or tetramethylene; examples of (1-6C)alkoxy-(1-6C)alkyl include methoxymethyl, ethoxymethyl and 2-methoxyethyl; examples of hydroxy-(2-6C)alkoxy include 2-hydroxyethoxy and 3-hydroxypropoxy; examples of (1-4C)alkylamino-(2-6C)alkoxy include 2-methylaminoethoxy and 2-ethylaminoethoxy; examples of di-(1-4C)alkylamino-(2-6C)alkoxy include 2-dimethylaminoethoxy and 2-diethylaminoethoxy; examples of phenyl(1-4C)alkyl include benzyl and phenethyl; examples of (1-4C)alkylcarbamoyl include methylcarbamoyl and ethylcarbamoyl; examples of di((1-4C)alkyl)carbamoyl include di(methyl)carbamoyl and di(ethyl)carbamoyl; examples of hydroxyimino(1-4C)alkyl include hydroxyiminomethyl, 2-(hydroxyimino)ethyl and 1-(hydroxyimino)ethyl; examples of (1-4C)alkoxyimino-(1-4C)alkyl include methoxyiminomethyl, ethoxyiminomethyl, 1-(methoxyimino)ethyl and 2-(methoxyimino)ethyl; examples of halo(1-4C)alkyl include, halomethyl, 1-haloethyl, 2-haloethyl, and 3-halopropyl; examples of nitro(1-4C)alkyl include nitromethyl, 1-nitroethyl, 2-nitroethyl and 3-nitropropyl; examples of amino(1-4C)alkyl include aminomethyl, 1-aminoethyl, 2-aminoethyl and 3-aminopropyl; examples of cyano(1-4C)alkyl include cyanomethyl, 1-cyanoethyl, 2-cyanoethyl and 3-cyanopropyl; examples of (1-4C)alkanesulfonamido include methanesulfonamido and ethanesulfonamido; examples of (1-4C)alkylaminosulfonyl include methylaminosulfonyl and ethylaminosulfonyl; and examples of di-1-4C)alkylaminosulfonyl include dimethylaminosulfonyl, diethylaminosulfonyl and N-methyl-N-ethylaminosulfonyl; examples of (1-4C)alkanesulfonyloxy include methylsulfonyloxy, ethylsulfonyloxy and propylsulfonyloxy; examples of (1-4C)alkanoyloxy include acetoxy; examples of (1-4C)alkylaminocarbonyl include methylaminocarbonyl and ethylaminocarbonyl; examples of di((1-4C)alkyl)aminocarbonyl include dimethylaminocarbonyl and diethylaminocarbonyl; examples of (3-8C)cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; examples of (4-7C)cycloalkyl include cyclobutyl, cyclopentyl and cyclohexyl; examples of di(N-(1-4C)alkyl)aminomethylimino include dimethylaminomethylimino and diethylaminomethylimino.
Particular values for AR2 include, for example, for those AR2 containing one heteroatom, furan, pyrrole, thiophene; for those AR2 containing one to four N atoms, pyrazole, imidazole, pyridine, pyrimidine, pyrazine, pyridazine, 1,2,3- and 1,2,4-triazole and tetrazole; for those AR2 containing one N and one O atom, oxazole, isoxazole and oxazine; for those AR2 containing one N and one S atom, thiazole and isothiazole; for those AR2 containing two N atoms and one S atom, 1,2,4- and 1,3,4-thiadiazole.
Particular examples of AR2a include, for example, dihydropyrrole (especially 2,5-dihydropyrrol-4-yl) and tetrahydropyridine (especially 1,2,5,6-tetrahydropyrid-4-yl).
Particular examples of AR2b include, for example, tetrahydrofuran, pyrrolidine, morpholine (preferably morpholino), thiomorpholine (preferably thiomorpholino), piperazine (preferably piperazino), imidazoline and piperidine, 1,3-dioxolan-4-yl, 1,3-dioxan-4-yl, 1,3-dioxan-5-yl and 1,4-dioxan-2-yl.
Particular values for AR3 include, for example, bicyclic benzo-fused systems containing a 5- or 6-membered heteroaryl ring containing one nitrogen atom and optionally 1-3 further heteroatoms chosen from oxygen, sulfur and nitrogen. Specific examples of such ring systems include, for example, indole, benzofuran, benzothiophene, benzimidazole, benzothiazole, benzisothiazole, benzoxazole, benzisoxazole, quinoline, quinoxaline, quinazoline, phthalazinc and cinnoline.
Other particular examples of AR3 include 5/5-, 5/6 and 6/6 bicyclic ring systems containing heteroatoms in both of the rings. Specific examples of such ring systems include, for example, purine and naphthyridine.
Further particular examples of AR3 include bicyclic heteroaryl ring systems with at least one bridgehead nitrogen and optionally a further 1-3 heteroatoms chosen from oxygen, sulfur and nitrogen. Specific examples of such ring systems include, for example, 3H-pyrrolo[1,2-a]pyrrole, pyrrolo[2,1-b]thiazole, 1H-imidazo[1,2-a]pyrrole, 1H-imidazo[1,2-a]imidazole, 1H,3H-pyrrolo[1,2-c]oxazole, 1H-imidazo[1,5-a]pyrrole, pyrrolo[1,2-b]isoxazole, imidazo[5,1-b]thiazole, imidazo[2,1-b]thiazole, indolizine, imidazo[1,2-a]pyridine, imidazo[1,5-a]pyridine, pyrazolo[1,5-a]pyridine, pyrrolo[1,2-b]pyridazine, pyrrolo[1,2-c]pyrimidine, pyrrolo[1,2-a]pyrazine, pyrrolo[1,2-a]pyrimidine, pyrido[2,1-c]-s-triazole, s-triazole[1,5-a]pyridine, imidazo[1,2-c]pyrimidine, imidazo[1,2-a]pyrazine, imidazo[1,2-a]pyrimidine, imidazo[1,5-a]pyrazine, imidazo[1,5-a]pyrimidine, imidazo[1,2-b]-pyridazine, s-triazolo[4,3-a]pyrimidine, imidazo[5,1-b]oxazole and imidazo[2,1-b]oxazole. Other specific examples of such ring systems include, for example, [1H]-pyrrolo[2,1-c]oxazine, [3H]-oxazolo[3,4-a]pyridine, [6H]-pyrrolo[2,1-c]oxazine and pyrido[2,1-c][1,4]oxazine. Other specific examples of 5/5-bicyclic ring systems are imidazooxazole or imidazothiazole, in particular imidazo[5,1-b]thiazole, imidazo[2,1-b]thiazole, imidazo[5,1-b]oxazole or imidazo[2,1-b]oxazole.
Particular examples of AR3a and AR3b include, for example, indoline, 1,3,4,6,9,9a-hexahydropyrido[2,1c][1,4]oxazin-8-yl, 1,2,3,5,8,8a-hexahydroimidazo[1,5a]pyridin-7-yl, 1,5,8,8a-tetrahydrooxazolo[3,4a]pyridin-7-yl, 1,5,6,7,8,8a-hexahydrooxazolo[3,4a]pyridin-7-yl, (7aS)[3H,5H]-1,7a-dihydropyrrolo[1,2c]oxazol-6-yl, (7aS)[5H]-1,2,3,7a-tetrahydropyrrolo[1,2c]imidazol-6-yl, (7aR)[3H,5H]-1,7a-dihydropyrrolo[1,2c]oxazol-6-yl, [3H,5H-pyrrolo[1,2-c]oxazol-6-yl, [5H]-2,3-dihydropyrrolo[1,2-c]imidazol-6-yl, [3H,5H]-pyrrolo[1,2-c]thiazol-6-yl, [3H,5H]-1,7a-dihydropyrrolo[1,2-c]thiazol-6-yl, [5H]-pyrrolo[1,2-c]imidazol-6-yl, [1H]-3,4,8,8a-tetrahydropyrrolo[2,1-c]oxazin-7-yl, [3H]-1,5,8,8a-tetrahydrooxazolo[3,4-a]pyrid-7-yl, (3H]-5,8-dihydroxazolo[3,4-a]pyrid-7-yl and 5,8-dihydroimidazo[1,5-a]pyrid-7-yl.
Particular values for AR4 include, for example, pyrrolo[a]quinoline, 2,3-pyrroloisoquinoline, pyrrolo[a]isoquinoline, 1H-pyrrolo[1,2-a]benzimidazole, 9H-imidazo[1,2-a]indole, 5H-imidazo[2,1-a]isoindole, 1H-imidazo[3,4-a]indole, imidazo[1,2-a]quinoline, imidazo[2,1-a]isoquinoline, imidazo[1,5-a]quinoline and imidazo[5,1-a]isoquinoline.
The nomenclature used is that found in, for example, xe2x80x9cHeterocyclic Compounds (Systems with bridgehead nitrogen), W. L. Mosby (Intercsience Publishers Inc., New York), 1961, Parts 1 and 2.
Where optional substituents are listed such substitution is preferably not geminal disubstitution unless stated otherwise. If not stated elsewhere suitable optional substituents for a particular group are those as stated for similar groups herein.
Suitable substituents on AR1, AR2, AR2a, AR2b, AR3, AR3a, AR3b, AR4, AR4a, CY1 and CY2 are (on an available carbon atom) up to three substituents independently selected from (1-4C)alkyl {optionally substituted by (preferably one) substituents selected independently from hydroxy, trifluoromethyl, (1-4C)alkyl S(O)qxe2x80x94 (q is 0, 1 or 2) (this last substituent preferably on AR1 only), 1-4C)alkoxy, (1-4C)alkoxycarbonyl, cyano, nitro, (1-4C)alkanoylamino, xe2x80x94CONRvRw or xe2x80x94NRvRw}, trifluoromethyl, hydroxy, halo, nitro, cyano, thiol, (1-4C)alkoxy, (1-4C)alkanoyloxy, dimethylaminomethyleneaminocarbonyl, di(Nxe2x80x94(1-4C)alkyl)aminomethylimino, carboxy, (1-4C)alkoxycarbonyl, (1-4C)alkanoyl, (1-4C)alkylSO2amino, (2-4C)alkenyl {optionally substituted by carboxy or (1-4C)alkoxycarbonyl}, (2-4C)alkynyl, (1-4C)alkanoylamino, oxo(xe2x95x90O), thioxo(xe2x95x90S), (1-4C)alkanoylamino {the (1-4C)alkanoyl group being optionally substituted by hydroxy}, (1-4C)alkyl S(O)qxe2x80x94 (q is 0, 1 or 2) {the (1-4C)alkyl group being optionally substituted by one or more groups independently selected from cyano, hydroxy and (1-4C)alkoxy}, xe2x80x94CONRvRw or xe2x80x94NRvRw [wherein Rv is hydrogen or (1-4C)alkyl; Rw is hydrogen or (1-4C)alkyl].
Further suitable substituents on AR1, AR2, AR2a, AR2b, AR3, AR3a, AR3b, AR4, AR4a, CY1 and CY2 (on an available carbon atom), and also on alkyl groups (unless indicated otherwise) are up to three substituents independently selected from trifluoromethoxy, benzoylamino, benzoyl, phenyl {optionally substituted by up to three substituents independently selected from halo, (1-4C)alkoxy or cyano}, furan, pyrrole, pyrazole, imidazole, triazole, pyrimidine, pyridazine, pyridine, isoxazole, oxazole, isothiazole, thiazole, thiophene, hydroxyimino(1-4C)alkyl, (1-4C)alkoxyimino(1-4C)alkyl, halo-(1-4C)alkyl, 1-4C)alkanesulfonamido, xe2x80x94SO2NRvRw [wherein Rv is hydrogen or 1-4C)alkyl; Rw is hydrogen or (1-4C)alkyl].
Preferable optional substituents on Ar2b as 1,3-dioxolan-4-yl, 1,3-dioxan-4-yl, 1,3-dioxan-5-yl or 1,4-dioxan-2-yl are mono- or disubstitution by substituents independently selected from (1-4C)alkyl (including geminal disubstitution), (1-4C)alkoxy, (1-4C)alkylthio, acetamido, (1-4C)alkanoyl, cyano, trifluoromethyl and phenyl].
Preferable optional substituents on CY1 and CY2 are mono- or disubstitution by substituents independently selected from (1-4C)alkyl (including geminal disubstitution), hydroxy, (1-4C)alkoxy, (1-4C)alkylthio, acetamido, (1-4C)alkanoyl, cyano, and trifluoromethyl.
Suitable substituents on AR2, AR2a, AR2b, AR3, AR3a, AR3b, AR4 and AR4a are (on an available nitrogen atom, where such substitution does not result in quaternization) (1-4C)alkyl, (1-4C)alkanoyl {wherein the (1-4C)alkyl and (1-4C)alkanoyl groups are optionally substituted by (preferably one) substituents independently selected from cyano, hydroxy, nitro, trifluoromethyl, (1-4C)alkyl S(O)qxe2x80x94 (q is 0, 1 or 2), (1-4C)alkoxy, (1-4C)alkoxycarbonyl, (1-4C)alkanoylamino, xe2x80x94CONRvRw or xe2x80x94NRvRw [wherein Rv is hydrogen or 1-4C)alkyl; Rw is hydrogen or 1-4C)alkyl]}, (2-4C)alkenyl, (2-4C)alkynyl, (1-4C)alkoxycarbonyl or oxo (to form an N-oxide).
Suitable pharmaceutically-acceptable salts include acid addition salts such as methanesulfonate, fumarate, hydrochloride, citrate, maleate, tartrate and (less preferably) hydrobromide. Also suitable are salts formed with phosphoric and sulfuric acid. In another aspect suitable salts are base salts such as an alkali metal salt for example sodium, an alkaline earth metal salt for example calcium or magnesium, an organic amine salt for example triethylamine, morpholine, N-methylpiperidine, N-ethylpiperidine, procaine, dibenzylamine, N,N-dibenzylethylamine, tris-(2-hydroxyethyl)amine, N-methyl d-glucamine and amino acids such as lysine. There may be more than one cation or anion depending on the number of charged functions and the valency of the cations or anions. A preferred pharmaceutically-acceptable salt is the sodium salt.
However, to facilitate isolation of the salt during preparation, salts which are less soluble in the chosen solvent may be preferred whether pharmaceutically-acceptable or not.
The compounds of the formula (I) may be administered in the form of a pro-drug which is broken down in the human or animal body to give a compound of the formula (I). A prodrug may be used to alter or improve the physical and/or pharmacokinetic profile of the parent compound and can be formed when the parent compound contains a suitable group or substituent which can be derivatised to form a prodrug. Examples of pro-drugs include in-vivo hydrolysable esters of a compound of the formula (I) or a pharmaceutically-acceptable salt thereof.
Various forms of prodrugs are known in the art, for examples see:
a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985);
b) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 xe2x80x9cDesign and Application of Prodrugsxe2x80x9d, by H. Bundgaard p. 113-191 (1991);
c) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992);
d) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); and
e) N. Kakeya, et al., Chem Pharm Bull, 32, 692 (1984).
An in-vivo hydrolysable ester of a compound of the formula (I) or a pharmaceutically-acceptable salt thereof containing carboxy or hydroxy group is, for example, a pharmaceutically-acceptable ester which is hydrolysed in the human or animal body to produce the parent acid or alcohol. Suitable pharmaceutically-acceptable esters for carboxy include (1-6C)alkoxymethyl esters for example methoxymethyl, (1-6C)alkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidyl esters, (3-8C)cycloalkoxycarbonyloxy(1-6C)alkyl esters for example 1-cyclohexylcarbonyloxyethyl; 1,3-dioxolan-2-onylmethyl esters for example 5-methyl-1,3-dioxolan-2-ylmethyl; and (1-6C)alkoxycarbonyloxyethyl esters for example 1-methoxycarbonyloxyethyl and may be formed at any carboxy group in the compounds of this invention.
An in-vivo hydrolysable ester of a compound of the formula (I) or a pharmaceutically-acceptable salt thereof containing a hydroxy group or groups includes inorganic esters such as phosphate esters (including phosphoramidic cyclic esters) and xcex1-acyloxyalkyl ethers and related compounds which as a result of the in-vivo hydrolysis of the ester breakdown to give the parent hydroxy group/s. Examples of xcex1-acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxymethoxy. A selection of in-vivo hydrolysable ester forming groups for hydroxy include (1-10C)alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, (1-10C)alkoxycarbonyl (to give alkyl carbonate esters), di-(1-4C)alkylcarbamoyl and Nxe2x80x94(di-(1-4C)alkylaminoethyl)-Nxe2x80x94(1-4C)alkylcarbamoyl (to give carbamates), di-(1-4C)alkylaminoacetyl and carboxyacetyl. Examples of substituents on benzoyl include chloromethyl or aminomethyl, 1-4C)alkylaminomethyl and di-((1-4C)alkyl)aminomethyl, and morpholino or piperazino linked from a ring nitrogen atom via a methylene linking group to the 3- or 4-position of the benzoyl ring.
Certain suitable in-vivo hydrolysable esters of a compound of the formula (I) are described within the definitions listed in this specification, for example esters described by the definition (Rc2d), and some groups within (Rc2c). Suitable in-vivo hydrolysable esters of a compound of the formula (I) are described as follows. For example, a 1,2-diol may be cyclised to form a cyclic ester of formula (PD1) or a pyrophosphate of formula (PD2): 
Particularly interesting are such cyclised pro-drugs when the 1,2-diol is on a (1-4C)alkyl chain linked to a carbonyl group in a substituent of formula Rc borne by a nitrogen atom in (TC4). Esters of compounds of formula (I) wherein the HOxe2x80x94 function/s in (PD1) and (PD2) are protected by (1-4C)alkyl, phenyl or benzyl are useful intermediates for the preparation of such pro-drugs.
Further in-vivo hydrolysable esters include phosporamidic esters, and also compounds of formula (I) in which any free hydroxy group independently forms a phosphoryl (npd is 1) or phosphiryl (npd is 0) ester of the formula (PD3): 
Useful intermediates for the preparation of such esters include compounds containing a group/s of formula (PD3) in which either or both of the xe2x80x94OH groups in (PD3) is independently protected by (1-4C)alkyl (such compounds also being interesting compounds in their own night), phenyl or phenyl-(1-4C)alkyl (such phenyl groups being optionally substituted by 1 or 2 groups independently selected from (1-4C)alkyl, nitro, halo and (1-4C)alkoxy).
Thus, prodrugs contain in groups such as (PD1), (PD2) and (PD3) may be prepared by reaction of a compound of formula (I) containing suitable hydroxy group/s with a suitably protected phosphorylating agent (for example, containing a chloro or dialkylamino leaving group), followed by oxidation (if necessary) and deprotection.
When a compound of formula (I) contains a number of free hydroxy group, those groups not being converted into a prodrug functionality may be protected (for example, using a t-butyl-dimethylsilyl group), and later deprotected. Also, enzymatic methods may be used to selectively phosphorylate or dephosphorylate alcohol functionalities.
Other interesting in-vivo hydrolysable esters include, for example, those in which Rc is defined by, for example, R14C(O)O(1-6C)alkyl-COxe2x80x94 (wherein R14 is for example, benzyloxy-(1-4C)alkyl, or phenyl). Suitable substituents on a phenyl group in such esters include, for example, 4-(1-4C)piperazino-(1-4C)alkyl, piperazino-(1-4C)alkyl and morpholino-(1-4C)alkyl.
Where pharmaceutically-acceptable salts of an in-vivo hydrolysable ester may be formed this is achieved by conventional techniques. Thus, for example, compounds containing a group of formula (PD1), (PD2) and/or (PD3) may ionise (partially or fully) to form salts with an appropriate number of counter-ions. Thus, by way of example, if an in-vivo hydrolysable ester prodrug of a compound of formula (I) contains two (PD3) groups, there are four HOxe2x80x94Pxe2x80x94 functionalities present in the overall molecule, each of which may form an appropriate salt (i.e. the overall molecule may form, for example, a mono-, di-, tri- or tetra-sodium salt).
The compounds of the present invention have a chiral centre at the C-5 position of the oxazolidinone ring. The pharmaceutically active enantiomer is of the formula (IA): 
The present invention includes the pure enantiomer depicted above or mixtures of the 5R and 5S enantiomers, for example a racemic mixture. If a mixture of enantiomers is used, a larger amount (depending upon the ratio of the enantiomers) will be required to achieve the same effect as the same weight of the pharmaceutically active enantiomer. For the avoidance of doubt the enantiomer depicted above is the 5R enantiomer.
Furthermore, some compounds of the formula (I) may have other chiral centres. It is to be understood that the invention encompasses all such optical and diastereo-isomers, and racemic mixtures, that possess antibacterial activity. It is well known in the art how to prepare optically-active forms (for example by resolution of the racemic form by recrystallisation techniques, by chiral synthesis, by enzymatic resolution, by biotransformation or by chromatographic separation) and how to determine antibacterial activity as described hereinafter.
The invention relates to all tautomeric forms of the compounds of the formula (I) that possess antibacterial activity.
It is also to be understood that certain compounds of the formula (I) can exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms which possess antibacterial activity.
It is also to be understood that certain compounds of the formula (I) may exhibit polymorphism, and that the invention encompasses all such forms which possess antibacterial activity.
As stated before, we have discovered a range of compounds that have good activity against a broad range of Gram-positive pathogens including organisms known to be resistant to most commonly used antibiotics. Physical and/or pharmacokinetic properties, for example increased stability to mammalian peptidase metabolism and a favourable toxicological profile are important features. The following compounds possess particularly favourable physical and/or pharmacokinetic properties and are preferred.
Particularly preferred compounds of the invention comprise a compound of formula (I) or of formula (IP), or a pharmaceutically-acceptable salt or an in-vivo hydrolysable ester thereof, wherein the substituents Q, X, HET, T and other substituents mentioned above have values disclosed hereinbefore, or any of the following values (which may be used where appropriate with any of the definitions and embodiments disclosed hereinbefore or hereinafter):
Preferably Q is selected from Q1, Q2, Q4, Q6 and Q9; especially Q1, Q2 and Q9; more particularly Q1 and Q2; and most preferably Q is Q1.
Preferably T is selected from (TAf), (TDb) or (TC); especially groups (TCb) and (TCc); more particularly (TC2), (TC3) and (TC4); and most preferably (TC5), (TC7) or (TC9), and most particularly (TC5). Especially preferred is each of these values of T when present in Q1 and Q2, particularly in Q1.
Preferable values for other substituents (which may be used where appropriate with any of the definitions and embodiments disclosed hereinbefore or hereinafter) are:
(a) Preferably X is xe2x80x94Oxe2x80x94;
(a1) In another aspect X is xe2x80x94Sxe2x80x94;
(b) Preferably HET is pyrazole, imidazole, oxazoic, isoxazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, isothiazole or 1,2,5-thiadiazole. Yet more preferably HET is pyrazol-3-yl, imidazol-2-yl, oxazol-2-yl, isoxazol-3-yl, 1,2,4-oxadiazol-3-yl, 1,3,4-oxadiazol-2-yl, isothiazol-3-yl or 1,2,5-thiadiazol-3-yl;
(b1) Especially preferred is HET as isoxazole (optionally substituted as disclosed hereinbefore), particularly isoxazol-3-yl;
(b2) In another embodiment HET is as defined hereinbefore or hereinafter, but excluding thiazole and thiadiazole; and in another embodiment HET is as defined hereinbefore or hereinafter, but excluding isothiazole and thiadiazole;
(b3) Preferably HET is unsubstituted;
(c) Preferably Rp is hydrogen;
(d) Preferably Rp1 and Rp2 are independently selected from hydrogen, (1-4C)alkyl, carboxy, (1-4C)alkoxycarbonyl, hydroxymethyl, (1-4C)alkoxymethyl or carbamoyl;
(e) Most preferably Rp1 and Rp2 are hydrogen;
(f) Preferably one of R2 and R3 is hydrogen and the other fluoro;
(g) In another aspect both R2 and R3 are fluoro;
(h) Preferably  greater than Axe2x80x94Bxe2x80x94 is of the formula  greater than Cxe2x95x90CHxe2x80x94 (i.e. Rr is preferably hydrogen) or  greater than Nxe2x80x94CH2xe2x80x94;
(i) Preferably D is xe2x80x94Oxe2x80x94 or  greater than NRcp;
(j) Preferably Rcp is AR, R13pCOxe2x80x94, R13pSO2xe2x80x94, R13pCSxe2x80x94;
(k) More preferably Rcp is AR (most preferably benzyl, pyrimidyl, pyridinyl, pyridazinyl or pyrazinyl) or R13pCOxe2x80x94 (especially R13pCOxe2x80x94);
(l) Preferably AR is 5- or 6-membered heteroaryl; more preferably AR is 6-membered heteroaryl, such as pyridinyl;
(m) Preferred substituents for phenyl and carbon atoms in heteroaryl (mono- and bicyclic) ring systems in AR, R14p and Ri include halo, (1-4C)alkyl, hydroxy, nitro, amino, cyano, (1-4C)alkylS(O)pxe2x80x94 and (1-4C)alkoxy;
(n) Preferably the optionally substituted ring systems in AR, R14p and Ri are unsubstituted;
(n1) In another embodiment in the definition of R13p in (PC) of embodiment (IP), 1,3-dioxolan-4-yl and 1,4-dioxan-2-yl are excluded.
(o) Preferably R13p is 1-4C)alkoxycarbonyl, hydroxy(1-4C)alkyl, 1-4C)alkyl (optionally substituted by one or two hydroxy groups, or by an (1-4C)alkanoyl group), (1-4C)alkylamino, dimethylamino(1-4C)alkyl, (1-4C)alkoxymethyl, (1-4C)alkanoylmethyl, (1-4C)alkanoyloxy(1-4C)alkyl, 1-5C)alkoxy or 2-cyanoethyl;
(p) More preferably R13p is 1,2-dihydroxyethyl, 1,3-dihydroxyprop-2-yl, 1,2,3-trihydroxyprop-1-yl, methoxycarbonyl, hydroxymethyl, methyl, methylamino, dimethylaminomethyl, methoxymethyl, acetoxymethyl, methoxy, methylthio, naphthyl, tert-butoxy or 2-cyanoethyl;
(p1) Yet more preferably R13p is 1,2-dihydroxyethyl, 1,3-dihydroxyprop-2-yl or 1,2,3-trihydroxyprop-1-yl;
(q) Preferred optional substituents for (1-10C)alkyl in R14p are hydroxy, cyano, amino, (1-4C)alkylamino, di((1-4C)alkyl)amino, 1-4C)alkylS(O)pxe2x80x94 (wherein p is 1 or 2), carboxy, (1-4C)alkoxycarbonyl, (1-4C)alkoxy, piperazino or morpholino;
(r) Preferred optional substituents for (1-6C)alkyl in R15p are hydroxy, (1-4C)alkoxy, cyano, amino, (1-4C)alkylamino, di((1-2C)alkyl)amino, (1-4C)alkylS(O)pxe2x80x94 (wherein p is 1 or 2);
(s) Preferably 5- or 6-membered heteroaryl in R14p is pyridinyl or imidazol-1-yl;
(t) Preferably R15p is (1-6C)alkyl; most preferably R15p is tert-butyl or methyl;
(u) Preferably R17p is cyano or fluoro;
(v) Preferably R16p is hydrogen;
(w) Preferably CY is naphthoxy, especially naphth-1-oxy or naphth-2-oxy.
Where preferable values are given for substituents in a compound of formula (IP), the corresponding substituents in a compound of formula (I) have the same preferable values (thus, for example, R13 and Rc in formula (I) correspond with Rcp and R13p in formula (IP), and similarly for groups D and G). For compounds of formula (I) preferred values for Rc are those in group (Rc2). The preferred values for R13p listed above for compounds of formula (IP) are also preferred values for R13 in compounds of formula (I). In the definition of (Rc2c) the AR2a, AR2b, AR3a and AR3b versions of AR2 and AR3 containing groups are preferably excluded.
In another aspect, HET is a C-linked 5-membered heteroaryl ring containing 2 or 3 heteratoms independently selected from N, O and S (with the proviso that there are no Oxe2x80x94O, Oxe2x80x94S, Sxe2x80x94S or Nxe2x80x94S bonds), which ring is optionally substituted on any available C atom (provided that when a N atom is adjacent to the X-link, there is no substitution on any C atom that is adjacent to this N atom) by 1 or 2 substituents independently selected from (1-4C)alkyl, amino, (1-4C)alkylamino, (1-4C)alkoxy and halogen, and/or on an available N atom (provided that the ring is not thereby quaternised), by (1-4C)alkyl.
In another aspect, HET is selected from the formulae (HET1) to (HET3) below: 
wherein A2 is carbon or nitrogen and B2 is O, S or N (with a maximum of 3 hetero atoms per ring), with carbon or nitrogen ring atoms being optionally substituted as described for HET hereinbefore (preferably with no substitution on any carbon atom that is adjacent to the specified N atom).
In another embodiment HET is as defined herein and also optionally substituted on an available suitable C atom by (1-4C)alkoxycarbonyl.
The above HET definitions are especially preferred in embodiment (IP), and with preferable value (n1) of R13p.
Especially preferred compounds of the present invention are of the formula (IB): 
wherein HET is isoxazol-3-yl, 1,2,4-oxadiazol-3-yl, isothiazol-3-yl or 1,2,5-thiadiazol-3-yl; R2 and R3 are independently hydrogen or fluoro; and Rp1 and Rp2 are independently hydrogen, hydroxy, bromo, (1-4C)alkyl, carboxy, (1-4C)alkoxycarbonyl, hydroxymethyl, (1-4C)alkoxymethyl or carbamoyl; or pharmaceutically-acceptable salts thereof.
Further especially preferred compounds of the invention are of the formula (IB) wherein HET is isoxazol-3-yl, 1,2,4-oxadiazol-3-yl, isothiazol-3-yl or 1,2,5-thiadiazol-3-yl; R2 and R3 are independently hydrogen or fluoro; and Rp1 and Rp2 are independently hydrogen, AR-oxymethyl or AR-thiomethyl (wherein AR is phenyl, phenyl-(1-4C)alkyl, naphthyl, furan, pyrrole, pyrazole, imidazole, triazole, pyrimidine, pyridazine, pyridine, isoxazole, oxazole, isothiazole, thiazole or thiophene); or pharmaceutically-acceptable salts thereof.
Of the above especially preferred compounds of the invention of the formula (IB), particularly preferred compounds are those wherein Rp1 and Rp2 arc hydrogen are particularly preferred.
Further, especially preferred compounds of the invention are of the formula (IC): 
wherein HET is isoxazol-3-yl, 1,2,4-oxadiazol-3-yl, isothiazol-3-yl or 1,2,5-thiadiazol-3-yl; R2 and R3 are independently hydrogen or fluoro; Rp1 and Rp2 are independently hydrogen, AR-oxymethyl or AR-thiomethyl (wherein AR is phenyl, phenyl-(1-4C)alkyl, naphthyl, furan, pyrrole, pyrazole, imidazole, triazole, pyrimidine, pyridazine, pyridine, isoxazole, oxazole, isothiazole, thiazole or thiophene), (1-4C)alkyl, carboxy, (1-4C)alkoxycarbonyl, hydroxymethyl, (1-4C)alkoxymethyl or carbamoyl and Rcp is cyano, pyrimidin-2-yl, 2-cyanoethenyl, 2-cyano-2-((1-4C)alkyl)ethenyl or Rcp is of the formula R13pCOxe2x80x94, R13pSO2xe2x80x94 or R13pCSxe2x80x94 (wherein R13p is hydrogen, (1-5C)alkyl [optionally substituted by one or more groups each independently selected from hydroxy and amino, or optionally monosubstituted by (1-4C)alkoxy, (1-4C)alkylS(O)qxe2x80x94, (1-4C)alkylamino, (1-4C)alkanoyl, naphthoxy, (2-6C)alkanoylamino or (1-4C)alkylS(O)pNHxe2x80x94 wherein p is 1 or 2 and q is 0, 1 or 2], imidazole, triazole, pyrimidine, pyridazine, pyridine, isoxazole, oxazole, isothiazole, thiazole, pyridoimidazole, pyrimidoimidazole, quinoxaline, quinazoline, phthalazine, cinnoline or naphthyridine, or R13p is of the formula R14pC(O)O(1-6C)alkyl wherein R14p is (1-6C)alkyl), or Rcp is of the formula RfC(xe2x95x90O)C(xe2x95x90O)xe2x80x94 wherein Rf is (1-6C)alkoxy; or pharmaceutically-acceptable salts thereof.
Of the above especially preferred compounds of the invention of the formula (IC), those wherein HET is isoxazol-3-yl, 1,2,4-oxadiazol-3-yl, isothiazol-3-yl or 1,2,5-thiadiazol-3-yl; R2 and R3 are independently hydrogen or fluoro; Rp1 and Rp2 are independently hydrogen, AR-oxymethyl or AR-thiomethyl (wherein AR is phenyl, phenyl-(1-4C)alkyl, naphthyl, furan, pyrrole, pyrazole, imidazole, triazole, pyrimidine, pyridazine, pyridine, isoxazole, oxazole, isothiazole, thiazole or thiophene), (1-4C)alkyl, carboxy, (1-4C)alkoxycarbonyl, hydroxymethyl, (1-4C)alkoxymethyl or carbamoyl and Rcp is cyano, pyrimidin-2-yl, 2-cyanoethenyl, 2-cyano-2-((1-4C)alkyl)ethenyl or Rcp is of the formula R13pCOxe2x80x94, R13pSO2xe2x80x94 or R13pCSxe2x80x94 (wherein R13p is hydrogen, 1-5C)alkyl [optionally substituted by one or more groups each independently selected from hydroxy and amino, or optionally monosubstituted by (1-4C)alkoxy, (1-4C)alkylS(O)q, (1-4C)alkylamino, (1-4C)alkanoyl, (2-6C)alkanoylamino or (1-4C)alkylS(O)pNHxe2x80x94 wherein p is 1 or 2 and q is 0, 1 or 2], pyridine, or R13p is of the formula R14pC(O)O(1-6C)alkyl wherein R14p is (1-6C)alkyl), or Rcp is of the formula RfC(xe2x95x90O)C(xe2x95x90O)xe2x80x94 wherein Rf is (1-6C)alkoxy; or pharmaceutically-acceptable salts thereof are further preferred.
Of the above especially preferred compounds of the invention of the formula (IC), particularly preferred compounds are those wherein HET is isoxazol-3-yl, 1,2,4-oxadiazol-3-yl, isothiazol-3-yl or 1,2,5-thiadiazol-3-yl; R2 and R3 are independently hydrogen or fluoro; Rp1 and Rp2 are hydrogen, and Rcp is pyridin-2-yl (optionally substituted with cyano) or Rcp is of the formula R13pCOxe2x80x94 (wherein R13p is hydrogen, 1,3-dioxolan-4-yl (optionally disubstituted with (1-4C)alkyl) or (1-5C)alkyl [optionally substituted by one or more hydroxy groups] or R13p is of the formula R14pC(O)O(1-6C)alkyl wherein R14p is (1-6C)alkyl)); or pharmaceutically-acceptable salts thereof.
Of the above especially preferred compounds of the invention of the formula (IC), particularly preferred compounds are those wherein Rcp is of the formula R13pCOxe2x80x94 (wherein R13p is hydrogen, 1,3-dioxolan-4-yl (optionally disubstituted with (1-4C)alkyl) or (1-5C)alkyl [substituted by two hydroxy groups]; or pharmaceutically-acceptable salts thereof.
In another aspect of the invention all of the compounds of formula (IB) or (IC) described above are further preferred when HET is isoxazol-3-yl, isothiazol-3-yl or 1,2,5-thiadiazol-3-yl.
In yet another aspect the invention relates to all of the compounds of formula (IB) or (IC) described above wherein HET is isoxazol-3-yl or 1,2,4-oxadiazol-3yl.
In yet another aspect the invention relates to all of the compounds of formula (IB) or (IC) described above wherein HET is isoxazol-3-yl.
In another aspect of the invention there are provided preferred compounds of the formula (IP) wherein xe2x80x94Xxe2x80x94HET is isoxazol-3-yloxy, 1,2,4-oxadiazol-3-yloxy, isothiazol-3-yloxy, 1,2,5-thiadiazol-3-yloxy;  greater than Axe2x80x94Bxe2x80x94 is  greater than Nxe2x80x94CH2xe2x80x94 and D is NRcp wherein Rcp is a 6-membered heteroaryl ring containing 1, 2 or 3 ring nitrogen atoms as the only ring heteroatoms, linked via a ring carbon atom and optionally substituted on a ring carbon atom by one, two or three substituents independently selected from (1-4C)alkyl, halo, trifluoromethyl, (1-4C)alkyl S(O)qxe2x80x94 (wherein q is 0, 1 or 2), 1-4C)alkylS(O)2amino, (1-4C)alkanoylamino, carboxy, hydroxy, amino, (1-4C)alkylamino, di-(1-4C)alkylamino, (1-4C)alkoxycarbonyl, carbamoyl, Nxe2x80x94(1-4C)alkylcarbamoyl, di-(Nxe2x80x94(1-4C)alkyl)carbamoyl, (1-4C)alkoxy, cyano or nitro, or pharmaceutically-acceptable salts thereof.
In all of the above aspects and preferred compounds of formula (IB) or (IC), in-vivo hydrolysable esters are preferred, especially phosphoryl esters (as defined by formula (PD3) with npd as 1).
In all of the above definitions the preferred compounds are as shown in formula (IA), i.e. the pharmaceutically active (5(R)) enantiomer.
Particular compounds of the present invention include the following (and the individual isomers where a mixture of isomers is possible):
5(R)-Isoxazol-3-yloxymethyl-3-(3-fluoro-4-(3,6-dihydro-(2H)-pyran-4-yl)phenyl)oxazolidin-2-one;
5(R)-(5-Methylisoxazol-3-yloxymethyl)-3-(3-fluoro-4-(3,6-dihydro-(2H)-pyran-4-yl)phenyl)oxazolidin-2-one;
5(R)-Isoxazol-3-yloxymethyl-3-(4-(1-(2,2-dimethyl-1,3-dioxolan-4(R,S)-ylcarbonyl)-5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)oxazolidin-2-one;
5(R)-Isoxazol-3-yloxymethyl-3-(4-(1-(2(R,S),3-dihydroxypropanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)-oxazolidin-2-one;
5(R)-Isoxazol-3-yloxymethyl-3-(4-(1-formyl-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)oxazolidin-2-one;
5(R)-Isoxazol-3-yloxymethyl-3-(4-(1-acetoxyacetyl-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)oxazolidin-2-one;
5(R)-Isoxazol-3-yloxymethyl-3-(4-(1-hydroxyacetyl-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)oxazolidin-2-one;
5(R)-Isoxazol-3-yloxymethyl-3-(4-(4-(5-cyanopyrid-2-yl )piperazin-1-yl)-3-fluorophenyl)oxazolidin-2-one;
5(R)-Isothiazol-3-yloxymethyl-3-(3-fluoro-4-(3,6-dihydro-(2H)-pyran-4-yl)phenyl)oxazolidin-2-one;
5(R)-(1,2,5-Thiadiazol-3-yloxymethyl)-3-(3-fluoro-4-(3,6-dihydro-(2H)-pyran-4-yl)phenyl)oxazolidin-2-one; or pharmaceutically-acceptable salts thereof.
Of the above compounds, especially preferred is (and the individual isomers thereof):
5(R)-Isoxazol-3-yloxymethyl-3-(4-(1-(2(R,S),3-dihydroxypropanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)-oxazolidin-2-one; or pharmaceutically-acceptable salts or in-vivo hydrolysable esters thereof.
Also preferred are the 3-fluorophenyl analogues of the particular 3,5-difluoro compounds mentioned above.
Other preferred Examples if not already specifically mentioned are Example Nos. 1, 2, 7, 14, 48, 148, 151 and 23.
Also preferred is the compound (and the individual isomers thereof):
5(R)-Isothiazol-3-yloxymethyl-3-(4-(1-(2(R,S),3-dihydroxypropanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3-fluorophenyl)-oxazolidin-2-one; or pharmaceutically-acceptable salts or in-vivo hydrolysable esters thereof.
Most particularly preferred Examples are Example Nos. 12, 18, 19, 20, 21 and 22 or pharmaceutically-acceptable salts. In-vivo hydrolysable esters of Examples 12 and 18 are preferred, especially phosphoryl esters.
Thus, preferred are the compounds, or pharmaceutically-acceptable salts thereof:
5(R)-Isoxazol-3-yloxymethyl-3-(4-(1-(2(S),3-diphosphoryl-propanoyl )-1,2,5,6-tetrahydropyrid-4-yl)-3-fluorophenyl)oxazolidin-2-one;
5(R)-Isoxazol-3-yloxymethyl-3-(4-(1-(2(S),3-diphosphoryl-propanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)oxazolidin-2-one.
Also preferred are the compounds, or pharmaceutically-acceptable salts thereof:
5(R)-Isoxazol-3-yloxymethyl-3-(4-(1-(2(S)-hydroxy-3-phosphoryl-propanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3-fluorophenyl)oxazolidin-2-one;
5(R)-Isoxazol-3-yloxymethyl-3-(4-(1-(2(S)-hydroxy-3-phosphoryl-propanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)oxazolidin-2-one.
Also preferred are the compounds, or pharmaceutically-acceptable salts thereof:
5(R)-Isoxazol-3-yloxymethyl-3-(4-(1-(3-hydroxy-2(S)-phosphoryl-propanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3-fluorophenyl)oxazolidin-2-one;
5(R)-Isoxazol-3-yloxymethyl-3-(4-(1-(3-hydroxy-2(S)-phosphoryl-propanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)oxazolidin-2-one.
Suitable pharmaceutically-acceptable salts of the last two named compounds and of Example Nos. 19, 20, 21 and 22 are the mono- and di-salts of the mono-phosphoryl ester compounds and the mono-, di-, tri- and tetra-salts of the di-phosphoryl ester compounds (Examples 19 and 21). Particularly preferred salts are the sodium salts.
Process Section:
In a further aspect the present invention provides a process for preparing a compound of formula (I) or a pharmaceutically-acceptable salt or an in-vivo hydrolysable ester thereof. It will be appreciated that during certain of the following processes certain substituents may require protection to prevent their undesired reaction. The skilled chemist will appreciate when such protection is required, and how such protecting groups may be put in place, and later removed.
For examples of protecting groups see one of the many general texts on the subject, for example, xe2x80x98Protective Groups in Organic Synthesisxe2x80x99 by Theodora Green (publisher: John Wiley and Sons). Protecting groups may be removed by any convenient method as described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with minimum disturbance of groups elsewhere in the molecule.
Thus, if reactants include, for example, groups such as amino, carboxy or hydroxy it may be desirable to protect the group in some of the reactions mentioned herein.
A suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl. The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an acyl group such as a t-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.
A suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl. The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
A suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a t-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
Examples of the use of resins as a protecting group are illustrated in Examples 135 and 136 herein.
The protecting groups may be removed at any convenient stage in the synthesis using conventional techniques well known in the chemical art.
A compound of the formula (I), or a pharmaceutically-acceptable salt or an in vivo hydrolysable ester thereof, may be prepared by any process known to be applicable to the preparation of chemically-related compounds. Such processes, when used to prepare a compound of the formula (I), or a pharmaceutically-acceptable salt or an in vivo hydrolysable ester thereof, are provided as a further feature of the invention and are illustrated by the following representative examples. Necessary starting materials may be obtained by standard procedures of organic chemistry (see, for example, Advanced Organic Chemistry (Wiley-Interscience), Jerry March). The preparation of such starting materials is described within the accompanying non-limiting Examples. Alternatively, necessary starting materials are obtainable by analogous procedures to those illustrated which are within the ordinary skill of an organic chemist. Information on the preparation of necessary starting materials or related compounds (which may be adapted to form necessary starting materials) may also be found in the following Patent and Application Publications, the contents of the relevant process sections of which are hereby incorporated herein by reference:
WO99/02525; WO98/54161; WO97/37980; WO97/30981 (and U.S. Pat. No. 5,736,545); WO97/21708 (and U.S. Pat. No. 5,719,154); WO97/10223; WO97/09328; WO96/35691; WO96/23788; WO96/15130; WO96/13502; WO95/25106 (and U.S. Pat. No. 5,668,286); WO95/14684 (and U.S. Pat. No. 5,652,238); WO95/07271 (and U.S. Pat. No. 5,688,792); WO94/13649; WO94/01110; WO93/23384 (and U.S. Pat. No. 5,547,950 and U.S. Pat. No. 5,700,799); WO93/09103 (and U.S. Pat. No. 5,565,571, U.S. Pat. No. 5,654,428, U.S. Pat. No. 5,654,435, U.S. Pat. No. 5,756,732 and U.S. Pat. No. 5,801,246); U.S. Pat. No. 5,231,188; U.S. Pat. No. 5,247,090; U.S. Pat. No. 5,523,403; WO97/27188; WO97/30995; WO97/31917; WO98/01447; WO98/01446; WO99/10342; WO99/10343; WO99/11642; European Patent Application Nos. 0,359,418 and 0,609,905; 0,693,491 A1 (and U.S. Pat. No. 5,698,574); 0,694,543 A1 (and AU 24985/95); 0,694,544 A1 (and CA 2,154,024); 0,697,412 A1 (and U.S. Pat. No. 5,529,998); 0,738,726 A1 (and AU 50735/96); 0,785,201 A1 (and AU 10123/97); German Patent Application Nos. DE 195 14 313 A1 (and U.S. Pat. No. 5,529,998); DE 196 01 264 A1 (and AU 10098/97); DE 196 01 265 A1 (and AU 10097/97); DE 196 04 223 A1 (and AU 12516/97); DE 196 49 095 A1 (and AU 12517/97).
The following Patent and Application Publications may also provide useful information and the contents of the relevant process sections are hereby incorporated herein by reference:
FR 2458547; FR 2500450(and GB 2094299, GB 2141716 and U.S. Pat. No. 4,476,136); DE 2923295 (and GB 2028306, GB 2054575, U.S. Pat. No. 4,287,351, U.S. Pat. No. 4,348,393, U.S. Pat. No. 4,413,001, U.S. Pat. No. 4,435,415 and U.S. Pat. No. 4,526,786), DE 3017499 (and GB 2053196, U.S. Pat. No. 4,346,102 and U.S. Pat. No. 4,372,967); U.S. Pat. No. 4,705,799; European Patent Application Nos. 0,312,000; 0,127,902; 0,184,170; 0,352,781; 0,316,594;
The skilled organic chemist will be able to use and adapt the information contained and referenced within the above references to obtain necessary starting materials.
Thus, the present invention also provides that the compounds of the formulae (I) and pharmaceutically-acceptable salts and in vivo hydrolysable esters thereof, can be prepared by a process (a) to (i) as follows (wherein the variables are as defined above unless otherwise stated):
(a) by modifying a substituent in or introducing a substituent into another compound of formula (I);
(b) by reaction of a compound of formula (II) 
wherein Yp is hydroxy with a compound of the formula (b1) HETxe2x80x94OH or (b2) HETxe2x80x94Lg, wherein Lg is a suitable leaving group;
(c) by reaction of a compound of formula (II) wherein Yp is a leaving group, for example halogen, mesylate or tosylate, with a metal alkoxide compound of the formula HETxe2x80x94OM where M is an alkali metal, or another metal, such as silver, known to promote O-alkylation;
(d) by reaction of a compound of the formula Qxe2x80x94Zp wherein Zp is an isocyanate or amine group with an epoxide of the formula CH2(O)CHxe2x80x94CH2Oxe2x80x94HET;
(e) when X is xe2x80x94Sxe2x80x94 by a process analogous to process (c) wherein (e1) a metal thioxide compound of the formula HETxe2x80x94SM where M is an alkali metal, or another metal, such as silver, known to promote S-alkylation; or (e2) alternatively by a process analogous to process (c) using HETxe2x80x94SH and a compound of formula (II) in which Yp is a suitable leaving group;
(f) when X is xe2x80x94SOxe2x80x94 or xe2x80x94SO2xe2x80x94 by oxidation of a compound wherein X is xe2x80x94Sxe2x80x94;
(g) by conversion to a non-quaternary compound of a compound of formula (I) in which the ring HET bears a quaternary nitrogen;
(h) when HET is an isoxazole ring by reaction of a compound of the formula (II) in which Yp is xe2x80x94Oxe2x80x94CHxe2x95x90Nxe2x80x94OH with an acetylene;
(i) by reaction of a urethane compound of formula (III) with a compound of formula (IV) 
wherein R21 is (1-6C)alkyl or benzyl; and thereafter if necessary
(i) removing any protecting groups; (ii) forming a pharmaceutically-acceptable salt; (iii) forming an in vivo hydrolysable ester.
General guidance on reaction conditions and reagents may be obtained in Advanced Organic Chemistry, 4th Edition, Jerry March (publisher: J. Wiley and Sons), 1992. Necessary starting materials may be obtained by standard procedures of organic chemistry, such as described in this process section, in the Examples section or by analogous procedures within the ordinary skill of an organic chemist. Certain references are also provided (see above) which describe the preparation of certain suitable starting materials, for particular example see International Patent Application Publication No. WO 97/37980, the contents of which are incorporated here by reference. Processes analogous to those described in the references may also be used by the ordinary organic chemist to obtain necessary starting materials.
(a) Methods for converting substituents into other substituents are known in the art. For example an alkylthio group may be oxidised to an alkylsulfinyl or alkylsulfonyl group, a cyano group reduced to an amino group, a nitro group reduced to an amino group, a hydroxy group alkylated to a methoxy group, a hydroxy group thiomethylated to an arylthiomethyl or a heteroarylthiomethyl group (see, for example, Tet.Lett., 585, 1972), a carbonyl group converted to a thiocarbonyl group (eg. using Lawsson""s reagent) or a bromo group converted to an alkylthio group. It is also possible to convert one Rc group into another Rc group as a final step in the preparation of a compound of the formula (I).
One compound of formula (I) may be converted into another compound of formula (I) by reacting a compound of formula (I) in which T is halo with a suitable compound to form another value of T. Thus, for example, T as halo may be displaced by suitable vinyl, aromatic, tropolone and nitrogen-linked systems as T by reaction using known Pd(0) coupling techniques.
Further examples of converting substituents into other substituents are contained in the accompanying non-limiting Examples.
(b1) When HETxe2x80x94OH is used reaction (b1) is performed under Mitsunobu conditions, for example, in the presence of tri-n-butylphosphine and diethyl azodicarboxylate (DEAD) in an organic solvent such as THF, and in the temperature range 0xc2x0 C.-60xc2x0 C., but preferably at ambient temperature. Details of Mitsunobu reactions are contained in Tet. Letts., 31, 699, (1990); The Mitsunobu Reaction, D. L. Hughes, Organic Reactions, 1992, Vol. 42, 335-656 and Progress in the Mitsunobu Reaction, D. L. Hughes, Organic Preparations and Procedures International, 1996, Vol. 28, 127-164.
(b2) When HETxe2x80x94Lg is used reaction (b2) is performed using a suitably reactive HET and under basic conditions (using a base such as 1,8-diazabicyclo[5,4,0]undec-7-ene) which are sufficiently mild not to destroy the oxazolidinone ring structure. The skilled organic chemist will appreciate which suitable leaving group Lg (such as chloro or bromo) and reaction conditions to use.
Compounds of the formula (II) wherein Yp is hydroxy may be obtained by reacting a compound of the formula (III) with a compound of formula (V): 
wherein R21 is (1-6C)alkyl or benzyl and R22 is (1-4C)alkyl or S(O)q(1-4C)alkyl where q is 0, 1 or 2. Preferably R22 is (1-4C)alkyl.
Compounds of the formula (II), (III) and (V) may be prepared by the skilled chemist, for example as described in International Patent Application Publication Nos. WO95/07271, WO97/27188, WO 97/30995, WO 98/01446 and WO 98/01446, the contents of which are hereby incorporated by reference, and by analogous processes.
If not commercially available, compounds of the formula HETxe2x80x94OH and HETxe2x80x94Lg may be prepared by procedures which are selected from standard chemical techniques, techniques which are analogous to the synthesis of known, structurally similar compounds, or techniques which are analogous to the procedures described in the Examples. For example, standard chemical techniques are as described in Houben Weyl, Methoden der Organische Chemie, E8a, Pt.I (1993), 45-225, B. J. Wakefield (for isoxazoles) and E8c, Pt.I (1994) 409-525, U. Kraatz (for 1,2,4-oxadiazoles). Also, for example, 3-hydroxyisoxazole may be prepared by cyclisation of CHxe2x89xa1Cxe2x80x94COxe2x80x94NHOH (prepared from CHxe2x89xa1Cxe2x80x94COxe2x80x94Oxe2x80x94(-4C)alkyl) as described in Chem.Pharm.Bull.Japan, 14, 92, (1966).
(c) and (e) Reactions (c) and (e) are performed conveniently at a temperature in the range 25-60xc2x0 C. in a solvent such as MAP or DMF.
A compound of the formula (II) wherein Yp is fluoro may be prepared by reacting a compound of the formula (II) wherein Yp is hydroxy (hiydroxy compound) with a fluorinating agent such as diethylaminosulfur trifluoride in an organic solvent such as dichloromethane in the temperature range of 0xc2x0 C. to ambient temperature.
When Yp is chloro, the compound of the formula (II) may be formed by reacting the hydroxy compound with a chlorinating agent. For example, by reacting the hydroxy compound with thionyl chloride, in a temperature range of ambient temperature to reflux, optionally in a chlorinated solvent such as dichloromethane or by reacting the hydroxy compound with carbon tetrachloride/triphenyl phosphine in dichloromethane, in a temperature range of 0xc2x0 C. to ambient temperature. A compound of the formula (II) wherein Yp is chloro or iodo may also be prepared from a compound of the formula (II) wherein Yp is mesyl ate or tosylate, by reacting the latter compound with lithium chloride or lithium iodide and crown ether, in a suitable organic solvent such as THF, in a temperature range of ambient temperature to reflux
When Yp is (1-4C)alkanesulfonyloxy or tosylate the compound (II) may be prepared by reacting the hydroxy compound with (1-4C)alkanesulfonyl chloride or tosyl chloride in the presence of a mild base such as triethylamine or pyridine.
Compounds of the formula HETxe2x80x94OM and HETxe2x80x94SM may be prepared by the skilled chemist from the corresponding HETxe2x80x94OH or HETxe2x80x94SH compound, using a suitable base, such as sodium hydride, silver carbonate, sodium carbonate or an alkoxide.
When X is xe2x80x94Sxe2x80x94 and a process is used that is analogous to process (c) but using HETxe2x80x94SH and a compound of formula (II) in which Yp is a suitable leaving group, a suitable leaving group is, for example, mesylate and a suitable base for the reaction is a base such as 1,8-diazabicyclo[5,4,0]undec-7-ene (see for example, Example 153).
(d) Reaction (d) is performed under conditions analogous to those described in the following references which disclose how suitable and analogous starting materials may be obtained.
Compounds of the formula Qxe2x80x94Zp wherein Zp is an isocyanate may be prepared by the skilled chemist, for example by analogous processes to those described in Walter A. Gregory et al in J.Med.Chem. 1990, 33, 2569-2578 and Chung-Ho Park et al in J.Med.Chem. 1992, 35, 1156-1165. Compounds of the formula Qxe2x80x94Zp wherein Zp is a urethane (see process (i)) may be prepared by the skilled chemist, for example by analogous processes to those described in International Patent Application Publication Nos. WO 97/30995 and WO 97/37980.
A similar reaction to reaction (d) may be performed in which Qxe2x80x94Zp wherein Zp is a amine group is reacted with the epoxide (optionally in the presence of an organic base), and the product is reacted with, for example, phosgene to form the oxazolidinone ring. Such reactions and the preparation of starting materials in within the skill of the ordinary chemist with reference to the above-cited documents disclosing analogous reactions and preparations.
Epoxides of the formula CH2(O)CHxe2x80x94CH2Oxe2x80x94HET may be prepared from the corresponding CH2xe2x95x90CHxe2x80x94CH2xe2x80x94Oxe2x80x94HET compound. Certain such epoxide and alkene intermediates are novel and are provided as a further feature of the invention. For example, when HET is isoxazol-3-yl, 3-(2,3-oxiranepropyloxy)isoxazole may be prepared from 3-allyloxyisoxazole. Asymmetric epoxidation may be used to give the desired optical isomer.
(f) When X is xe2x80x94SOxe2x80x94 or xe2x80x94SO2xe2x80x94 the oxidation of a compound wherein X is xe2x80x94Sxe2x80x94 may be achieved by oxidising with standard reagents known in the art for the oxidation of a thio group to a sulfinyl or sulfonyl group. For example, a thio group may be oxidised to a sulfinyl group with a peracid such as m-chloroperoxybenzoic acid and oxidising agents such as potassium permanganate can be used to convert a thio group to a sulfonyl group.
(g) The conversion to a non-quaternary compound of a compound of formula (I) in which the ring HET bears a quaternary nitrogen may be achieved under thermal conditions suitable to achieve elimination of the quaternary group (for example, a methyl group will be eliminated as a methyl halide).
A compound of formula (I) in which the ring HET bears a quaternary nitrogen may be prepared in a similar manner to the conditions described for reaction (c), although a suitably quaternised HET compound, substituted in the alpha position next to nitrogen by a leaving group (such as halogen), and a compound of the formula (II) in which Yp is xe2x80x94OH or xe2x80x94SH, is used. Such starting materials are readily prepared by the ordinary organic chemist.
A compound of formula (I) in which the ring HET bears a quaternary nitrogen may also be prepared in a similar manner to the conditions described in Chem.Pharm.Bull.Japan, 27, 2415-2423, (1979), by reaction of an N-alkylated HETxe2x80x94OH or HETxe2x80x94SH compound in the keto-form (with the keto (oxo or thioxo) group in the alpha position next to nitrogen) with a compound of formula (II) in which Yp is a leaving group such as mesylate.
(h) When the HET ring is isoxazole it may be built up as a final step from a compound of the formula (II) in which Yp is xe2x80x94Oxe2x80x94CHxe2x95x90Nxe2x80x94OH by reaction under standard conditions with an acetylene (see for example, Acta Chem. Scand 47, 1004, 1993).
(i) A compound of formula (III) is reacted with a compound of formula (IV) using similar conditions to those for reaction of a compound of the formula (III) with a compound of formula (V) described above. If not commercially available, the preparation of suitable starting materials of formulae (III) and (IV) is as described above, or by using analogous processes.
The removal of any protecting groups, the formation of a pharmaceutically-acceptable salt and/or the formation of an in vivo hydrolysable ester are within the skill of an ordinary organic chemist using standard techniques. Furthermore, details on the these steps, for example the preparation of in-vivo hydrolysable ester prodrugs has been provided in the section above on such esters, and in certain of the following non-limiting Examples.
When an optically active form of a compound of the formula (I) is required, it may be obtained by carrying out one of the above procedures using an optically active starting material (formed, for example, by asymmetric induction of a suitable reaction step), or by resolution of a racemic form of the compound or intermediate using a standard procedure, or by chromatographic separation of diastereoisomers (when produced). Enzymatic techniques may also be useful for the preparation of optically active compounds and/or intermediates.
Similarly, when a pure regioisomer of a compound of the formula (I) is required, it may be obtained by carrying out one of the above procedures using a pure regioisomer as a starting material, or by resolution of a mixture of the regioisomers or intermediates using a standard procedure.
According to a further feature of the invention there is provided a compound of the formula (I), or a pharmaceutically-acceptable salt, or in-vivo hydrolysable ester thereof for use in a method of treatment of the human or animal body by therapy.
According to a further feature of the present invention there is provided a method for producing an antibacterial effect in a warm blooded animal, such as man, in need of such treatment, which comprises administering to said animal an effective amount of a compound of the present invention, or a pharmaceutically-acceptable salt, or in-vivo hydrolysable ester thereof.
The invention also provides a compound of the formula (I), or a pharmaceutically-acceptable salt, or in-vivo hydrolysable ester thereof, for use as a medicament; and the use of a compound of the formula (I) of the present invention, or a pharmaceutically-acceptable salt, or in-vivo hydrolysable ester thereof, in the manufacture of a medicament for use in the production of an antibacterial effect in a warm blooded animal, such as man.
In order to use a compound of the formula (I), an in-vivo hydrolysable ester or a pharmaceutically-acceptable salt thereof, including a pharmaceutically-acceptable salt of an in-vivo hydrolysable ester, (hereinafter in this section relating to pharmaceutical composition xe2x80x9ca compound of this inventionxe2x80x9d) for the therapeutic (including prophylactic) treatment of mammals including humans, in particular in treating infection, it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
Therefore in another aspect the present invention provides a pharmaceutical composition which comprises a compound of the formula (I), an in-vivo hydrolysable ester or a pharmaceutically-acceptable salt thereof, including a pharmaceutically-acceptable salt of an in-vivo hydrolysable ester, and a pharmaceutically-acceptable diluent or carrier.
The pharmaceutical compositions of this invention may be administered in standard manner for the disease condition that it is desired to treat, for example by oral, rectal or parenteral administration. For these purposes the compounds of this invention may be formulated by means known in the art into the form of, for example, tablets, capsules, aqueous or oily solutions or suspensions, (lipid) emulsions, dispersible powders, suppositories, ointments, creams, aerosols (or sprays), drops and sterile injectable aqueous or oily solutions or suspensions.
In addition to the compounds of the present invention the pharmaceutical composition of this invention may also contain or be co-administered (simultaneously, sequentially or separately) with one or more known drugs selected from other clinically useful antibacterial agents (for example, xcex2-lactams or aminoglycosides) and/or other anti-infective agents (for example, an antifungal triazole or amphotericin). These may include carbapenems, for example meropenem or imipenem, to broaden the therapeutic effectiveness. Compounds of this invention may also contain or be co-administered with bactericidal/permeability-increasing protein (BPI) products or efflux pump inhibitors to improve activity against gram negative bacteria and bacteria resistant to antimicrobial agents.
A suitable pharmaceutical composition of this invention is one suitable for oral administration in unit dosage form, for example a tablet or capsule which contains between 1 mg and 1 g of a compound of this invention, preferably between 100 mg and 1 g of a compound. Especially preferred is a tablet or capsule which contains between 50 mg and 800 mg of a compound of this invention, particularly in the range 100 mg to 500 mg.
In another aspect a pharmaceutical composition of the invention is one suitable for intravenous, subcutaneous or intramuscular injection, for example an injection which contains between 0.1% w/v and 50% w/v (between 1 mg/ml and 500 mg/ml) of a compound of this invention.
Each patient may receive, for example, a daily intravenous, subcutaneous or intramuscular dose of 0.5 mgkgxe2x88x921 to 20 mgkgxe2x88x921 of a compound of this invention, the composition being administered 1 to 4 times per day. In another embodiment a daily dose of 5 mgkgxe2x88x921 to 20 mgkgxe2x88x921 of a compound of this invention is administered. The intravenous, subcutaneous and intramuscular dose may be given by means of a bolus injection. Alternatively the intravenous dose may be given by continuous infusion over a period of time. Alternatively each patient may receive a daily oral dose which may be approximately equivalent to the daily parenteral dose, the composition being administered 1 to 4 times per day.
A pharmaceutical composition to be dosed intravenously may contain advantageously (for example to enhance stability) a suitable bactericide, antioxidant or reducing agent, or a suitable sequestering agent.
In the above other, pharmaceutical composition, process, method, use and medicament manufacture features, the alternative and preferred embodiments of the compounds of the invention described herein also apply.
Antibacterial Activity:
The pharmaceutically-acceptable compounds of the present invention are useful antibacterial agents having a good spectrum of activity in vitro against standard Gram-positive organisms, which are used to screen for activity against pathogenic bacteria. Notably, the pharmaceutically-acceptable compounds of the present invention show activity against enterococci, pneumococci and methicillin resistant strains of S.aureus and coagulase negative staphylococci. The antibacterial spectrum and potency of a particular compound may be determined in a standard test system.
The (antibacterial) properties of the compounds of the invention may also be demonstrated and assessed in-vivo in conventional tests, for example by oral and/or intravenous dosing of a compound to a warm-blooded mammal using standard techniques.
The following results were obtained on a standard in-vitro test system. The activity is described in terms of the minimum inhibitory concentration (MIC) determined by the agar-dilution technique with an inoculum size of 104 CFU/spot. Typically, compounds are active in the range 0.01 to 256 xcexcg/ml.
Staphylococci were tested on agar, using an inoculum of 104 CFU/spot and an incubation temperature of 37xc2x0 C. for 24 hoursxe2x80x94standard test conditions for the expression of methicillin resistance.
Streptococci and enterococci were tested on agar supplemented with 5% defibrinated horse blood, an inoculum of 104 CFU/spot and an incubation temperature of 37xc2x0 C. in an atmosphere of 5% carbon dioxide for 48 hoursxe2x80x94blood is required for the growth of some of the test organisms.
Certain Reference Examples described hereinafter (for example, Reference Examples 9, 10, 11, 30, 38 and 39) may also possess useful activity.